brain research 1601 (2015) 85–91
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Constriction and dysfunction of pial arterioles after regional hemorrhage in the subarachnoid space$ Chun-xi Wang1, Yi-xing Lin, Guang-bin Xie, Ji-xin Shi, Meng-liang Zhoun Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, China
art i cle i nfo
ab st rac t
Article history:
Increasing evidence indicates that poor outcomes after brain hemorrhage, especially after
Accepted 8 January 2015
subarachnoid hemorrhage (SAH), can be attributed largely to dysfunction of the cerebral
Available online 15 January 2015
microcirculation. However, the cause of this dysfunction remains unclear. Here, we
Keywords:
investigated changes in the cerebral microcirculation after regional hemorrhage in the
Subarachnoid hemorrhage
subarachnoid space using the closed cranial window technique in mice. A single pial
Microcirculation
arteriole on the surface of the brain was punctured to induce a regional hemorrhage in the
Pial arterioles
subarachnoid space. Physiological parameters were monitored during the procedure, and
Vasoreactivity
microvessel diameter was measured after hemorrhage. The vasoreactivity of the arterioles
Mice
in response to hypercapnia as well as to topical application of the vasodilator acetylcholine (ACh) and S-nitroso-N-acetyl-penicillamine (SNAP) were assessed. The constriction of pial arterioles was detected without changes in other physiological parameters. Decreased reactivity of pial arterioles to all of the applied vasodilatory stimuli was observed after hemorrhage. Our results indicate that regional hemorrhage in the subarachnoid space can induce the vasospasm of microvessels and also reduce the vasoreactivity of pial arterioles. & 2015 Published by Elsevier B.V.
1.
Introduction
Subarachnoid hemorrhage (SAH) is a subtype of stroke that accounts for approximately 5% of all strokes (Graf and Nibbelink, 1974; King, 1997). Almost 40% of patients with SAH die within 30 days after onset (Ingall et al., 1989; Kissela et al., 2002), and despite improvements in the diagnosis and treatment of SAH, the mortality rate has not changed (Connolly et al., 2012). Vasospasm of the large conducting cerebral arteries is regarded as the major cause of delayed ☆
ischemic neurological deficits (DINDs), which result in morbidity and mortality in patients with SAH (Macdonald et al., 2007). However, this type of vasospasm cannot fully account for the occurrence of DINDs, because symptoms of cerebral ischemia can occur in patients without evidence of angiographic vasospasm (vasospasm of the large conducting cerebral arteries) (Graham et al., 1983; Pennings et al., 2004). Clinical and experimental studies have indicated that cerebral microcirculatory dysfunction is involved in the pathophysiology of DINDs after SAH (Friedrich et al., 2012; Herz
This work was supported by grants from The National Natural Science Foundation of China (NSFC): No. 81000503(ML Zhou). Corresponding author. Fax: þ86 25 51805396. E-mail address: [email protected] (M.-l. Zhou). 1 Wang CX and Lin YX are joint first authors and contributed equally.
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http://dx.doi.org/10.1016/j.brainres.2015.01.012 0006-8993/& 2015 Published by Elsevier B.V.
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brain research 1601 (2015) 85–91
et al., 1975; Pennings et al., 2009; Pennings et al., 2004; Sun et al., 2009). Because dysfunction of the cerebral microcirculation results in cerebral ischemia after SAH, leading to poor outcomes and occasionally death, detection of the underlying mechanisms is required to improve the outcomes for SAH patients. Many potential causes have been suggested for the dysfunction of cerebral microcirculation after SAH, such as elevated intracranial pressure (Asano and Sano, 1977; Schubert et al., 2009) and the vasoactive properties of blood products that are also regarded as the cause of vasospasm of the large cerebral arteries (Clark and Sharp, 2006; Dreier et al., 2002; Loftspring, 2010). To discover the mechanisms underlying cerebral microcirculation dysfunction, it is necessary to elucidate the contributions of different factors. Hence, we investigated the effects of regional hemorrhage (without intracranial pressure elevation) of pial arterioles in the cerebral microcirculation in mice.
2.
Hg during the resting state, with an increase to 55–65 mm Hg during hypercapnia. No statistical differences were found in the physiological parameters including PaCO2 and partial pressure of O2 (PaO2) between two groups (Table 1). These results show that vasoreactivity to hypercapnia was reduced
Results
2.1. Changes in pial vessel diameter after regional hemorrhage The constriction of pial arterioles in the hemorrhage region was observed in all animals and could be detected from 3 h after hemorrhage (Figs. 1 and 2). The average pial arteriole diameter was decreased by 31.5%, 32.2%, 32.2%, and 25.6% at 3, 12, 24, and 48 h post-hemorrhage, respectively, compared to the baseline value. No significant changes were detected in the diameter of pial venules exposed to blood in subarachnoid space. These results indicate that regional hemorrhage in the subarachnoid space caused the pial arteries to constrict immediately and continually for at least 48 h.
2.2.
Responses to hypercapnia
No significant differences were observed in the baseline vascular diameters between the sham-operated and hemorrhage groups (Fig. 3A). In contrast, the response of the pial arterioles to hypercapnia was significantly reduced at 24 h after hemorrhage. The vasoreactivity was decreased by 48.1% (from a value of 36.2% to 18.8%, Fig. 3B). In both groups, the partial pressure of CO2 (PaCO2) was maintained at 25–35 mm
Fig. 2 – (A) Pial arteriole diameter after hemorrhage. Significant constriction was found from 3–48 h after hemorrhage (po0.01 vs. baseline). Constricted arterioles were observed as early as 3 h after hemorrhage and until 48 h after hemorrhage. They tended to recover at 48 h after hemorrhage. (B) No significant changes in the diameters of venules were observed after hemorrhage.
Fig. 1 – (A) A single pial arteriole was punctured in the cranial window to induce regional hemorrhage in the subarachnoid space. (B) Images were captured through the cranial window at 24 h after induction of hemorrhage. The arteriole was constricted in a multifocal (bean-string) pattern (arrow).
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in mice with regional hemorrhage, and this reduction could not be attributed to differences in the extent of PaCO2 change after induced hypercapnia, other physiological parameters, or baseline vascular diameter.
decreased by 57.2% (to 17.9%, Fig. 4B), which implicates dysfunction of endothelial cells (ECs) in pial arteries after hemorrhage.
2.4. 2.3.
Responses to acetylcholine(ACh)
The baseline vascular diameter did not differ significantly between the sham-operated and hemorrhage groups (Fig. 4A). Reduced vasoreactivity to the endothelium-dependent vasodilator ACh was observed at 24 h after hemorrhage. Compared to the vasoreactivity in the sham-operated animals (41.8%), the vasoreactivity in the hemorrhage group was
Fig. 3 – (A) No difference was found between the baseline vascular responses of pial arteriole in the sham-operated and hemorrhage groups (p ¼0.20). (B) The dilatory response of pial arterioles to hypercapnia was 36.2% in the sham group compared to only 18.8% in the hemorrhage group (po0.01). Vasoreactivity (%)¼ average diameter after hypercapnia/baseline diameter 100.
Responses to S-nitroso-N-acetyl-penicillamine (SNAP)
Again, the baseline vascular diameter did not differ significantly between the sham-operated and hemorrhage groups (Fig. 5A). A greater reduction in vessel response to topical application of the smooth muscle cell (SMC)-dependent vasodilator SNAP was observed in mice in the hemorrhage group compared to that in the sham-operated group. The average vasodilation of pial arterioles in response to SNAP was 41.6%, but this was decreased
Fig. 4 – (A) No difference was found between the baseline vascular responses of the pial arterioles in the shamoperated and hemorrhage groups (p¼ 0.43). (B) The vasodilation (%) of pial arterioles in response to the ECdependent agent ACh was 41.8% in the sham-operated group and only 17.9% in the hemorrhage group (po0.01). Vasoreactivity (%) ¼average diameter after ACh application/ baseline diameter 100.
Table 1 – PaCO2 and PaO2 pre- and post-hypercapnia Group
Sham Hemorrhage
n
6 6
PaCO2
PaO2
Pre
Post
Pre
Post
29.671.3 29.771.0
60.071.8 58.973.4
159.074.8 161.175.7
160.574.8 161.675.0
Blood Gases were analyzed before (Pre) and 5 min after (Post) induction of hypercapnia. Data indicate mean7SEM.
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functioning of the brain. The general principles of fluid dynamics apply in that CBF(F) is directly related to pressure (P) and inversely affected by resistance (R) (Kulik et al., 2008): F¼
Fig. 5 – (A) No difference was found between the baseline vascular responses of the pial arterioles in the shamoperated and hemorrhage groups (p¼ 0.22). (B) The vasodilation (%) of pial arterioles in response to the SMCdependent agent SNAP was 41.6% in the sham-operated group and only 23.9% in the hemorrhage group (po0.01). Vasoreactivity (%)¼ average diameter after SNAP application/baseline diameter 100. to 23.9% in the mice subjected to regional brain hemorrhage (Fig. 5B). These results demonstrated the dysfunction of SMCs in pial arterioles after pial arteriole hemorrhage.
3.
Discussion
The main findings of the present study are as follows: 1) the constriction of pial arterioles rather than pial venules was observed after regional hemorrhage in the subarachnoid space; 2) the reactivity of pial arterioles to hypercapnia was significantly decreased after regional hemorrhage compared to after sham operation in mice; and 3) the vessel responses to the EC-dependent vasodilator Ach and the SMC-dependent vasodilator SNAP were both decreased after regional brain hemorrhage. Our results confirm the dysfunction of cerebral microcirculation after pial arteriole hemorrhage in mice and demonstrate that the dysfunction of both ECs and SMCs may cause this microcirculatory dysfunction in the brain after regional hemorrhage in subarachnoid space. The cerebral microcirculation maintains the normal cerebral blood flow (CBF), which is critical for the normal
P R
Of course, resistance is inversely related to the 4th power of the diameter of the vessel (Kobari et al., 1984). Thus, small reductions in the diameter of arterioles can induce significant increases in resistance and ultimately could result in a dramatic decrease in CBF. If constriction of the arterioles occurs in patients with SAH, it is reasonable to speculate that this could induce a drop in CBF and subsequently cause ischemic brain injury. Uhl et al. reported moderate-to-severe segmental constriction in arterioles in SAH patients during aneurysm surgery using an orthogonal polarization spectral imaging system (Uhl et al., 2003), and these findings were confirmed by Pennings et al. using the same methods in SAH patients (Pennings et al., 2004). In the present study, our results showed the constriction of arterioles after pial arteriole hemorrhage. Similar observations have been described in other SAH models (Friedrich et al., 2012; Herz et al., 1975; Morii et al., 1986; Parfenova et al., 1993; Sehba et al., 2007; Sun et al., 2009), but the present study has several advantages compared to these previous studies. First, in our study, large amounts of subarachnoid autologous blood were present in the perivascular space. This model induced a perivascular environment similar to that observed in humans after SAH (Pennings et al., 2004; Uhl et al., 2003). Second, mice were used in this study, which makes it possible to employ transgenic mice to explore the underlying mechanisms. In the present study, we found that the constriction of the microvessels occurred in arterioles rather than venules. In addition, the constriction of arterioles began early (o3 h after SAH) and lasted at least 48 h after hemorrhage. Also, the arterioles constricted by about 30% compared to baseline values. This reduction in vessel diameter could be severe enough to cause a significant decrease in CBF according to the Hagen-Poiseuille law, by which a reduction in vessel diameter by 30% results in a reduction of flow by approximately 80% (Friedrich et al., 2012). Assuming that the constriction of arterioles occurs immediately after SAH in the whole brain instead of a limited region, the decrease in CBF would be enough to cause the clinical symptoms of cerebral ischemia before the development of delayed cerebral vasospasm. An acute decrease in CBF after SAH also could induce cerebral ischemia and brain edema and ultimately result in DINDs. In addition to the diameter of arterioles, the function of arterioles is also very important in the regulation of CBF. Our results indicate the occurrence of vasomotor impairment after regional SAH. We observed an impaired vascular response to hypercapnia at 24 h after hemorrhage, which suggests that microcerebrovascular autoregulation is profoundly impaired after hemorrhage. Some studies have reported similar observations using papaverine in humans with SAH (Pennings et al., 2009). Next, we tested the responses to the EC-dependent vasodilator Ach and SMC-dependent vasodilator SNAP to explore the cellular events responsible for cerebrovascular dysfunction after brain hemorrhage. Our results demonstrate impairment of SNAP-induced vasodilation in mice after hemorrhage, which
brain research 1601 (2015) 85–91
suggests abnormal SMC function after hemorrhage. Similarly, abnormal EC function in our hemorrhage model was found using the EC-dependent vasodilator Ach. Taken together, these results imply that the dysfunction of both ECs and SMCs contributes to the dysfunction of the microcirculation after SAH. However, further studies are required to confirm these effects in different experimental models of SAH as well as to elucidate the underlying mechanisms. In contrast to our findings, Britz et al. obtained conflicting results using CO2, adenosine, and sodium nitroprusside (SNP) in an endovascular filament model of SAH in rats (Britz et al., 2007). They found that CO2 reactivity was unaffected by SAH. This discrepancy may be due to differences in specific experimental methodologies, including variations in anesthesia, the method of cerebrovascular assessment, and the applied vasoactive stimuli as well as differences in animal species (Table 2). More importantly, in the endovascular filament model, no perivascular subarachnoid blood could be detected at the surface of the parietal cortex where the cranial windows were installed. In our animals, the microvessels detected were surrounded by blood, which is similar to the situation in human SAH patients. Several previous studies have investigated changes in vasoreactivity after SAH (Pennings et al., 2009; Sobey et al., 1996; Sobey and Quan 1999; Vatter et al., 2007). However, most of these studies focused on the responses of basilar arteries to vasodilators after SAH (Sobey et al., 1996; Sobey and Quan, 1999; Vatter et al., 2007), which are related to the cerebral vasospasm of large arteries. In contrast, our study provided evidence of impaired cerebral microcirculation through observation of changes in the pial arterioles. Similar to our findings, Park et al. also reported impaired responses of microvessels to the endothelium-dependent dilator in their ex vivo study (Park et al., 2001). In summary, our results demonstrate the constriction and dysfunction of pial arterioles after regional hemorrhage in subarachnoid space. Further studies are needed to identify the underlying mechanisms.
4.
Experimental procedure
4.1.
Animal preparation
The animal use and care protocols, including all procedures, were approved by the Animal Care and Use Committee of
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Jinling Hospital and conformed to the Guide for the Care and Use of Laboratory Animals of the U.S. National Institutes of Health. Three–four-month-old male C57BL/6J mice were purchased from the Animal Center of the Chinese Academy of Sciences (Shanghai, China) for use in the present study. They were acclimated in a humidified room and maintained on the standard diet at the Animal Center of Jinling Hospital for ten days before experiments. The temperature in both the feeding room and the operation room was maintained at approximately 25 1C.
4.2. Cranial window installation and induction of hemorrhage The microcirculation of the right parietal cortex was visualized through a closed cranial window, which was implanted as previously reported with modification (Brendza et al., 2005; Han et al., 2008). Briefly, a 4-mm-diameter craniotomy was performed with a water-cooled dental drill in the right parietal bone after the skin was removed. A single pial arteriole was punctured with the tip of a forceps after the skull cap was removed. This method induced regional bleeding in subarachnoid space. Next, two lines of tubes that could be used as an inlet and outlet for vasodilator infusion into the cerebrospinal fluid bathing the pial vessels were inserted through the bone wax. Then, the craniotomy was sealed to the bone with a coverslip using dental cement, and the resulting space filled with artificial cerebrospinal fluid (125 mM NaCl, 26 mM NaHCO3, 1.25 mM NaH2PO4, 2.5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, and 25 mM glucose). After completion of the procedures, the mice were returned to their cages for recovery with access to food and water ad libitum.
4.3.
Experimental design
The first set of experiments was performed to assess the morphological changes in vessels after SAH. One pial arteriole and one pial venule with diameters of 15–20 μm were selected for analysis. The vessel diameter in each mouse (n¼ 12) was measured at five time points: baseline (during the procedure before regional hemorrhage induction) and 3, 12, 24, and 48 h post-hemorrhage. At each time point, the animal was placed under the microscope, and images were taken through the cranial windows after the mice were
Table 2 – Methodologic differences between the present study and that of Britz et al. (2007)
Animals Model Anesthetic PaCO2 before/after CO2 inhalation Concentration of CO2 inhaled Duration of CO2 inhalation
The present study
The study of Britz et al.
Mice Regional hemorrhage in subarachnoid space with rupture of pial arteriole α-chloralose(80 mg/kg, i.p.) 29.771.0/58.973.4
Rats Endovascular filament model of subarachnoid hemorrhage α-chloralose þurethane(50 and 500 mg/kg, respectively, i.p.) 32.9.273.7/46.276.1
5% CO2/30% O2
6% CO2/34% O2
5 min
2 min
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brain research 1601 (2015) 85–91
anesthetized with α-chloralose (80 mg/kg, intraperitoneally [i. p.], Sigma-Aldrich, St. Louis, MO, USA). The second set of experiments was designed to explore the vasoreactivity to hypercapnia, ACh, and SNAP after hemorrhage. Two groups of mice were used: a shamoperated group (n¼ 6) and a hemorrhage group (n ¼6). In both groups, vasoreactivity (the vascular response to vasoactive stimuli) was tested at 24 h after cranial window implantation.
4.4.
Vasoreactivity to hypercapnia
The responses of the vessels to hypercapnia were detected to assess the ability of vascular regulation after hemorrhage. The mice were anesthetized with isoflurane (Hospira, Lake Forest, IL, USA) and α-chloralose (80 mg/kg, i.p.) and ventilated at a stroke volume of 5 ml/kg body weight and ventilation rate of 150 strokes/min with a rodent ventilator (Harvard Apparatus Co., Holliston, MA, USA). Body temperature was maintained at 37 1C using a heating pad (Harvard Apparatus Co.). An arterial catheter was placed into the femoral artery for measurement of the mean arterial blood pressure (MBP) and blood gases. The isoflurane was reduced gradually to zero before the mouse was placed under the microscope. After an equilibration period, an image of the region with a clear pial arteriole (15–20 μm in diameter) without injury and located in the region of bleeding was taken for comparison to baseline conditions while the animals were ventilated with 30% O2-containing air. Subsequently, changes in PaCO2 were induced by ventilating the animal with 5% CO2/30% O2containing air for 5 min. Blood gases were analyzed before hypercapnia, 4 min after hypercapnia, and 4 min after recovery. Images were taken through the cranial windows after completion of hypecapnia.
4.5.
Vasoreactivity to ACh
The endothelium-dependent vasodilator ACh (100 μM; SigmaAldrich) was infused into the cranial window at a rate of 20 μl/min for 5 min after the baseline image was taken. Upon completion of Ach infusion, another image was taken through the cranial window, and artificial cerebrospinal fluid was then infused for 10–20 min or until the vessel diameter returned to its baseline value.
4.6.
Vasoreactivity to SNAP
The vascular SMC-dependent vasodilator SNAP (500 μM; SigmaAldrich) was infused into the cranial window at a rate of 20 μl/min for 5 min after the baseline image was taken. Upon completion of SNAP infusion, another image was taken through the cranial window, and artificial cerebrospinal fluid was then infused for 10–20 min or until the vessel diameter returned to its baseline value. The order of vasodilatory agent treatment was randomly assigned.
4.7.
Vessel diameter measurement
Vessel diameter was determined using Diamtrak software (Tim Neild, Monash University, Melbourne, Australia) as described previously (Han et al., 2008). Briefly, averaged vessel
diameters across a 25-μm longitudinal segment (at least four consecutive segments were measured per artery) of the vessels of interest were analyzed before (baseline) and after exposure to hypercapnia, Ach, or SNAP. The vasoreactivity was calculated as the percent (%) vasodilation relative to the baseline vessel diameter.
4.8.
Statistical analysis
Data are expressed as means7standard error of the mean (SEM). Comparisons among multiple groups were performed by one-way analysis of variance followed by the Dunnett's multiple comparison method. P values o0.05 were considered significant.
Sources of funding This work was supported by grants from the National Natural Science Foundation of China (NSFC): No. 81000503(ML Zhou).
Conflict(s)-of-interest/Disclosure(s) none
r e f e r e n c e s
Asano, T., Sano, K., 1977. Pathogenetic role of no-reflow phenomenon in experimental subarachnoid hemorrhage in dogs. J. Neurosurg. 46, 454–466. Brendza, R.P., Bacskai, B.J., Cirrito, J.R., Simmons, K.A., Skoch, J.M., Klunk, W.E., Mathis, C.A., Bales, K.R., Paul, S.M., Hyman, B.T., Holtzman, D.M., 2005. Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J. Clin. Invest. 115, 428–433. Britz, G.W., Meno, J.R., Park, I.S., Abel, T.J., Chowdhary, A., Nguyen, T.S., Winn, H.R., Ngai, A.C., 2007. Time-dependent alterations in functional and pharmacological arteriolar reactivity after subarachnoid hemorrhage. Stroke 38, 1329–1335. Clark, J.F., Sharp, F.R., 2006. Bilirubin oxidation products (BOXes) and their role in cerebral vasospasm after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 26, 1223–1233. Connolly Jr., E.S., Rabinstein, A.A., Carhuapoma, J.R., Derdeyn, C.P., Dion, J., Higashida, R.T., Hoh, B.L., Kirkness, C.J., Naidech, A.M., Ogilvy, C.S., Patel, A.B., Thompson, B.G.,, Vespa, P., 2012. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 43, 1711–1737. Dreier, J.P., Windmuller, O., Petzold, G., Lindauer, U., Einhaupl, K.M., Dirnagl, U., 2002. Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats. Neurosurgery 51, 1457–1465 (discussion 1465-7). Friedrich, B., Muller, F., Feiler, S., Scholler, K., Plesnila, N., 2012. Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J. Cereb. Blood Flow Metab. 32, 447–455. Graf, C.J., Nibbelink, D.W., 1974. Cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Report on a
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randomized treatment study. 3. Intracranial surgery. Stroke 5, 557–601. Graham, D.I., Macpherson, P., Pitts, L.H., 1983. Correlation between angiographic vasospasm, hematoma, and ischemic brain damage following SAH. J. Neurosurg. 59, 223–230. Han, B.H., Zhou, M.L., Abousaleh, F., Brendza, R.P., Dietrich, H.H., Koenigsknecht-Talboo, J., Cirrito, J.R., Milner, E., Holtzman, D.M., Zipfel, G.J., 2008. Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gammasecretase inhibition. J. Neurosci. 28, 13542–13550. Herz, D.A., Baez, S., Shulman, K., 1975. Pial microcirculation in subarachnoid hemorrhage. Stroke 6, 417–424. Ingall, T.J., Whisnant, J.P., Wiebers, D.O., O’Fallon, W.M., 1989. Has there been a decline in subarachnoid hemorrhage mortality. Stroke 20, 718–724. King Jr., J.T., 1997. Epidemiology of aneurysmal subarachnoid hemorrhage. Neuroimaging Clin. N. Am. 7, 659–668. Kissela, B.M., Sauerbeck, L., Woo, D., Khoury, J., Carrozzella, J., Pancioli, A., Jauch, E., Moomaw, C.J., Shukla, R., Gebel, J., Fontaine, R., Broderick, J., 2002. Subarachnoid hemorrhage: a preventable disease with a heritable component. Stroke 33, 1321–1326. Kobari, M., Gotoh, F., Fukuuchi, Y., Tanaka, K., Suzuki, N., Uematsu, D., 1984. Blood flow velocity in the pial arteries of cats, with particular reference to the vessel diameter. J. Cereb. Blood Flow Metab. 4, 110–114. Kulik, T., Kusano, Y., Aronhime, S., Sandler, A.L., Winn, H.R., 2008. Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology 55, 281–288. Loftspring, M.C., 2010. Iron and early brain injury after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 30, 1791–1792. Macdonald, R.L., Pluta, R.M., Zhang, J.H., 2007. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat. Clin. Pract. Neurol. 3, 256–263. Morii, S., Ngai, A.C., Winn, H.R., 1986. Reactivity of rat pial arterioles and venules to adenosine and carbon dioxide: with detailed description of the closed cranial window technique in rats. J. Cereb. Blood Flow Metab. 6, 34–41. Parfenova, H., Shibata, M., Leffler, C.W., 1993. Subarachnoid blood causes pial arteriolar constriction in newborn pigs. Stroke 24, 1729–1734.
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Park, K.W., Metais, C., Dai, H.B., Comunale, M.E., Sellke, F.W., 2001. Microvascular endothelial dysfunction and its mechanism in a rat model of subarachnoid hemorrhage. Anesth. Analg. 92, 990–996. Pennings, F.A., Bouma, G.J., Ince, C., 2004. Direct observation of the human cerebral microcirculation during aneurysm surgery reveals increased arteriolar contractility. Stroke 35, 1284–1288. Pennings, F.A., Albrecht, K.W., Muizelaar, J.P., Schuurman, P.R., Bouma, G.J., 2009. Abnormal responses of the human cerebral microcirculation to papaverin during aneurysm surgery. Stroke 40, 317–320. Schubert, G.A., Seiz, M., Hegewald, A.A., Manville, J., Thome, C., 2009. Acute hypoperfusion immediately after subarachnoid hemorrhage: a xenon contrast-enhanced CT study. J. Neurotrauma. 26, 2225–2231. Sehba, F.A., Friedrich Jr., V., Makonnen, G., Bederson, J.B., 2007. Acute cerebral vascular injury after subarachnoid hemorrhage and its prevention by administration of a nitric oxide donor. J. Neurosurg. 106, 321–329. Sobey, C.G., Quan, L., 1999. Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage. Am. J. Physiol. 277, H1718–H1724. Sobey, C.G., Heistad, D.D., Faraci, F.M., 1996. Effect of subarachnoid hemorrhage on dilatation of rat basilar artery in vivo. Am. J. Physiol. 271, H126–H132. Sun, B.L., Zheng, C.B., Yang, M.F., Yuan, H., Zhang, S.M., Wang, L.X., 2009. Dynamic alterations of cerebral pial microcirculation during experimental subarachnoid hemorrhage. Cell Mol. Neurobiol. 29, 235–241. Uhl, E., Lehmberg, J., Steiger, H.J., Messmer, K., 2003. Intraoperative detection of early microvasospasm in patients with subarachnoid hemorrhage by using orthogonal polarization spectral imaging. Neurosurgery 52, 1307–1315 (disacussion 1315-7). Vatter, H., Weidauer, S., Dias, S., Preibisch, C., Ngone, S., Raabe, A., Zimmermann, M., Seifert, V., 2007. Persistence of the nitric oxide-dependent vasodilator pathway of cerebral vessels after experimental subarachnoid hemorrhage. Neurosurgery 60, 179–187 (discussion 187-8).
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Research Report
Constriction and dysfunction of pial arterioles after regional hemorrhage in the subarachnoid space$ Chun-xi Wang1, Yi-xing Lin, Guang-bin Xie, Ji-xin Shi, Meng-liang Zhoun Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, China
art i cle i nfo
ab st rac t
Article history:
Increasing evidence indicates that poor outcomes after brain hemorrhage, especially after
Accepted 8 January 2015
subarachnoid hemorrhage (SAH), can be attributed largely to dysfunction of the cerebral
Available online 15 January 2015
microcirculation. However, the cause of this dysfunction remains unclear. Here, we
Keywords:
investigated changes in the cerebral microcirculation after regional hemorrhage in the
Subarachnoid hemorrhage
subarachnoid space using the closed cranial window technique in mice. A single pial
Microcirculation
arteriole on the surface of the brain was punctured to induce a regional hemorrhage in the
Pial arterioles
subarachnoid space. Physiological parameters were monitored during the procedure, and
Vasoreactivity
microvessel diameter was measured after hemorrhage. The vasoreactivity of the arterioles
Mice
in response to hypercapnia as well as to topical application of the vasodilator acetylcholine (ACh) and S-nitroso-N-acetyl-penicillamine (SNAP) were assessed. The constriction of pial arterioles was detected without changes in other physiological parameters. Decreased reactivity of pial arterioles to all of the applied vasodilatory stimuli was observed after hemorrhage. Our results indicate that regional hemorrhage in the subarachnoid space can induce the vasospasm of microvessels and also reduce the vasoreactivity of pial arterioles. & 2015 Published by Elsevier B.V.
1.
Introduction
Subarachnoid hemorrhage (SAH) is a subtype of stroke that accounts for approximately 5% of all strokes (Graf and Nibbelink, 1974; King, 1997). Almost 40% of patients with SAH die within 30 days after onset (Ingall et al., 1989; Kissela et al., 2002), and despite improvements in the diagnosis and treatment of SAH, the mortality rate has not changed (Connolly et al., 2012). Vasospasm of the large conducting cerebral arteries is regarded as the major cause of delayed ☆
ischemic neurological deficits (DINDs), which result in morbidity and mortality in patients with SAH (Macdonald et al., 2007). However, this type of vasospasm cannot fully account for the occurrence of DINDs, because symptoms of cerebral ischemia can occur in patients without evidence of angiographic vasospasm (vasospasm of the large conducting cerebral arteries) (Graham et al., 1983; Pennings et al., 2004). Clinical and experimental studies have indicated that cerebral microcirculatory dysfunction is involved in the pathophysiology of DINDs after SAH (Friedrich et al., 2012; Herz
This work was supported by grants from The National Natural Science Foundation of China (NSFC): No. 81000503(ML Zhou). Corresponding author. Fax: þ86 25 51805396. E-mail address: [email protected] (M.-l. Zhou). 1 Wang CX and Lin YX are joint first authors and contributed equally.
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http://dx.doi.org/10.1016/j.brainres.2015.01.012 0006-8993/& 2015 Published by Elsevier B.V.
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et al., 1975; Pennings et al., 2009; Pennings et al., 2004; Sun et al., 2009). Because dysfunction of the cerebral microcirculation results in cerebral ischemia after SAH, leading to poor outcomes and occasionally death, detection of the underlying mechanisms is required to improve the outcomes for SAH patients. Many potential causes have been suggested for the dysfunction of cerebral microcirculation after SAH, such as elevated intracranial pressure (Asano and Sano, 1977; Schubert et al., 2009) and the vasoactive properties of blood products that are also regarded as the cause of vasospasm of the large cerebral arteries (Clark and Sharp, 2006; Dreier et al., 2002; Loftspring, 2010). To discover the mechanisms underlying cerebral microcirculation dysfunction, it is necessary to elucidate the contributions of different factors. Hence, we investigated the effects of regional hemorrhage (without intracranial pressure elevation) of pial arterioles in the cerebral microcirculation in mice.
2.
Hg during the resting state, with an increase to 55–65 mm Hg during hypercapnia. No statistical differences were found in the physiological parameters including PaCO2 and partial pressure of O2 (PaO2) between two groups (Table 1). These results show that vasoreactivity to hypercapnia was reduced
Results
2.1. Changes in pial vessel diameter after regional hemorrhage The constriction of pial arterioles in the hemorrhage region was observed in all animals and could be detected from 3 h after hemorrhage (Figs. 1 and 2). The average pial arteriole diameter was decreased by 31.5%, 32.2%, 32.2%, and 25.6% at 3, 12, 24, and 48 h post-hemorrhage, respectively, compared to the baseline value. No significant changes were detected in the diameter of pial venules exposed to blood in subarachnoid space. These results indicate that regional hemorrhage in the subarachnoid space caused the pial arteries to constrict immediately and continually for at least 48 h.
2.2.
Responses to hypercapnia
No significant differences were observed in the baseline vascular diameters between the sham-operated and hemorrhage groups (Fig. 3A). In contrast, the response of the pial arterioles to hypercapnia was significantly reduced at 24 h after hemorrhage. The vasoreactivity was decreased by 48.1% (from a value of 36.2% to 18.8%, Fig. 3B). In both groups, the partial pressure of CO2 (PaCO2) was maintained at 25–35 mm
Fig. 2 – (A) Pial arteriole diameter after hemorrhage. Significant constriction was found from 3–48 h after hemorrhage (po0.01 vs. baseline). Constricted arterioles were observed as early as 3 h after hemorrhage and until 48 h after hemorrhage. They tended to recover at 48 h after hemorrhage. (B) No significant changes in the diameters of venules were observed after hemorrhage.
Fig. 1 – (A) A single pial arteriole was punctured in the cranial window to induce regional hemorrhage in the subarachnoid space. (B) Images were captured through the cranial window at 24 h after induction of hemorrhage. The arteriole was constricted in a multifocal (bean-string) pattern (arrow).
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in mice with regional hemorrhage, and this reduction could not be attributed to differences in the extent of PaCO2 change after induced hypercapnia, other physiological parameters, or baseline vascular diameter.
decreased by 57.2% (to 17.9%, Fig. 4B), which implicates dysfunction of endothelial cells (ECs) in pial arteries after hemorrhage.
2.4. 2.3.
Responses to acetylcholine(ACh)
The baseline vascular diameter did not differ significantly between the sham-operated and hemorrhage groups (Fig. 4A). Reduced vasoreactivity to the endothelium-dependent vasodilator ACh was observed at 24 h after hemorrhage. Compared to the vasoreactivity in the sham-operated animals (41.8%), the vasoreactivity in the hemorrhage group was
Fig. 3 – (A) No difference was found between the baseline vascular responses of pial arteriole in the sham-operated and hemorrhage groups (p ¼0.20). (B) The dilatory response of pial arterioles to hypercapnia was 36.2% in the sham group compared to only 18.8% in the hemorrhage group (po0.01). Vasoreactivity (%)¼ average diameter after hypercapnia/baseline diameter 100.
Responses to S-nitroso-N-acetyl-penicillamine (SNAP)
Again, the baseline vascular diameter did not differ significantly between the sham-operated and hemorrhage groups (Fig. 5A). A greater reduction in vessel response to topical application of the smooth muscle cell (SMC)-dependent vasodilator SNAP was observed in mice in the hemorrhage group compared to that in the sham-operated group. The average vasodilation of pial arterioles in response to SNAP was 41.6%, but this was decreased
Fig. 4 – (A) No difference was found between the baseline vascular responses of the pial arterioles in the shamoperated and hemorrhage groups (p¼ 0.43). (B) The vasodilation (%) of pial arterioles in response to the ECdependent agent ACh was 41.8% in the sham-operated group and only 17.9% in the hemorrhage group (po0.01). Vasoreactivity (%) ¼average diameter after ACh application/ baseline diameter 100.
Table 1 – PaCO2 and PaO2 pre- and post-hypercapnia Group
Sham Hemorrhage
n
6 6
PaCO2
PaO2
Pre
Post
Pre
Post
29.671.3 29.771.0
60.071.8 58.973.4
159.074.8 161.175.7
160.574.8 161.675.0
Blood Gases were analyzed before (Pre) and 5 min after (Post) induction of hypercapnia. Data indicate mean7SEM.
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functioning of the brain. The general principles of fluid dynamics apply in that CBF(F) is directly related to pressure (P) and inversely affected by resistance (R) (Kulik et al., 2008): F¼
Fig. 5 – (A) No difference was found between the baseline vascular responses of the pial arterioles in the shamoperated and hemorrhage groups (p¼ 0.22). (B) The vasodilation (%) of pial arterioles in response to the SMCdependent agent SNAP was 41.6% in the sham-operated group and only 23.9% in the hemorrhage group (po0.01). Vasoreactivity (%)¼ average diameter after SNAP application/baseline diameter 100. to 23.9% in the mice subjected to regional brain hemorrhage (Fig. 5B). These results demonstrated the dysfunction of SMCs in pial arterioles after pial arteriole hemorrhage.
3.
Discussion
The main findings of the present study are as follows: 1) the constriction of pial arterioles rather than pial venules was observed after regional hemorrhage in the subarachnoid space; 2) the reactivity of pial arterioles to hypercapnia was significantly decreased after regional hemorrhage compared to after sham operation in mice; and 3) the vessel responses to the EC-dependent vasodilator Ach and the SMC-dependent vasodilator SNAP were both decreased after regional brain hemorrhage. Our results confirm the dysfunction of cerebral microcirculation after pial arteriole hemorrhage in mice and demonstrate that the dysfunction of both ECs and SMCs may cause this microcirculatory dysfunction in the brain after regional hemorrhage in subarachnoid space. The cerebral microcirculation maintains the normal cerebral blood flow (CBF), which is critical for the normal
P R
Of course, resistance is inversely related to the 4th power of the diameter of the vessel (Kobari et al., 1984). Thus, small reductions in the diameter of arterioles can induce significant increases in resistance and ultimately could result in a dramatic decrease in CBF. If constriction of the arterioles occurs in patients with SAH, it is reasonable to speculate that this could induce a drop in CBF and subsequently cause ischemic brain injury. Uhl et al. reported moderate-to-severe segmental constriction in arterioles in SAH patients during aneurysm surgery using an orthogonal polarization spectral imaging system (Uhl et al., 2003), and these findings were confirmed by Pennings et al. using the same methods in SAH patients (Pennings et al., 2004). In the present study, our results showed the constriction of arterioles after pial arteriole hemorrhage. Similar observations have been described in other SAH models (Friedrich et al., 2012; Herz et al., 1975; Morii et al., 1986; Parfenova et al., 1993; Sehba et al., 2007; Sun et al., 2009), but the present study has several advantages compared to these previous studies. First, in our study, large amounts of subarachnoid autologous blood were present in the perivascular space. This model induced a perivascular environment similar to that observed in humans after SAH (Pennings et al., 2004; Uhl et al., 2003). Second, mice were used in this study, which makes it possible to employ transgenic mice to explore the underlying mechanisms. In the present study, we found that the constriction of the microvessels occurred in arterioles rather than venules. In addition, the constriction of arterioles began early (o3 h after SAH) and lasted at least 48 h after hemorrhage. Also, the arterioles constricted by about 30% compared to baseline values. This reduction in vessel diameter could be severe enough to cause a significant decrease in CBF according to the Hagen-Poiseuille law, by which a reduction in vessel diameter by 30% results in a reduction of flow by approximately 80% (Friedrich et al., 2012). Assuming that the constriction of arterioles occurs immediately after SAH in the whole brain instead of a limited region, the decrease in CBF would be enough to cause the clinical symptoms of cerebral ischemia before the development of delayed cerebral vasospasm. An acute decrease in CBF after SAH also could induce cerebral ischemia and brain edema and ultimately result in DINDs. In addition to the diameter of arterioles, the function of arterioles is also very important in the regulation of CBF. Our results indicate the occurrence of vasomotor impairment after regional SAH. We observed an impaired vascular response to hypercapnia at 24 h after hemorrhage, which suggests that microcerebrovascular autoregulation is profoundly impaired after hemorrhage. Some studies have reported similar observations using papaverine in humans with SAH (Pennings et al., 2009). Next, we tested the responses to the EC-dependent vasodilator Ach and SMC-dependent vasodilator SNAP to explore the cellular events responsible for cerebrovascular dysfunction after brain hemorrhage. Our results demonstrate impairment of SNAP-induced vasodilation in mice after hemorrhage, which
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suggests abnormal SMC function after hemorrhage. Similarly, abnormal EC function in our hemorrhage model was found using the EC-dependent vasodilator Ach. Taken together, these results imply that the dysfunction of both ECs and SMCs contributes to the dysfunction of the microcirculation after SAH. However, further studies are required to confirm these effects in different experimental models of SAH as well as to elucidate the underlying mechanisms. In contrast to our findings, Britz et al. obtained conflicting results using CO2, adenosine, and sodium nitroprusside (SNP) in an endovascular filament model of SAH in rats (Britz et al., 2007). They found that CO2 reactivity was unaffected by SAH. This discrepancy may be due to differences in specific experimental methodologies, including variations in anesthesia, the method of cerebrovascular assessment, and the applied vasoactive stimuli as well as differences in animal species (Table 2). More importantly, in the endovascular filament model, no perivascular subarachnoid blood could be detected at the surface of the parietal cortex where the cranial windows were installed. In our animals, the microvessels detected were surrounded by blood, which is similar to the situation in human SAH patients. Several previous studies have investigated changes in vasoreactivity after SAH (Pennings et al., 2009; Sobey et al., 1996; Sobey and Quan 1999; Vatter et al., 2007). However, most of these studies focused on the responses of basilar arteries to vasodilators after SAH (Sobey et al., 1996; Sobey and Quan, 1999; Vatter et al., 2007), which are related to the cerebral vasospasm of large arteries. In contrast, our study provided evidence of impaired cerebral microcirculation through observation of changes in the pial arterioles. Similar to our findings, Park et al. also reported impaired responses of microvessels to the endothelium-dependent dilator in their ex vivo study (Park et al., 2001). In summary, our results demonstrate the constriction and dysfunction of pial arterioles after regional hemorrhage in subarachnoid space. Further studies are needed to identify the underlying mechanisms.
4.
Experimental procedure
4.1.
Animal preparation
The animal use and care protocols, including all procedures, were approved by the Animal Care and Use Committee of
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Jinling Hospital and conformed to the Guide for the Care and Use of Laboratory Animals of the U.S. National Institutes of Health. Three–four-month-old male C57BL/6J mice were purchased from the Animal Center of the Chinese Academy of Sciences (Shanghai, China) for use in the present study. They were acclimated in a humidified room and maintained on the standard diet at the Animal Center of Jinling Hospital for ten days before experiments. The temperature in both the feeding room and the operation room was maintained at approximately 25 1C.
4.2. Cranial window installation and induction of hemorrhage The microcirculation of the right parietal cortex was visualized through a closed cranial window, which was implanted as previously reported with modification (Brendza et al., 2005; Han et al., 2008). Briefly, a 4-mm-diameter craniotomy was performed with a water-cooled dental drill in the right parietal bone after the skin was removed. A single pial arteriole was punctured with the tip of a forceps after the skull cap was removed. This method induced regional bleeding in subarachnoid space. Next, two lines of tubes that could be used as an inlet and outlet for vasodilator infusion into the cerebrospinal fluid bathing the pial vessels were inserted through the bone wax. Then, the craniotomy was sealed to the bone with a coverslip using dental cement, and the resulting space filled with artificial cerebrospinal fluid (125 mM NaCl, 26 mM NaHCO3, 1.25 mM NaH2PO4, 2.5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, and 25 mM glucose). After completion of the procedures, the mice were returned to their cages for recovery with access to food and water ad libitum.
4.3.
Experimental design
The first set of experiments was performed to assess the morphological changes in vessels after SAH. One pial arteriole and one pial venule with diameters of 15–20 μm were selected for analysis. The vessel diameter in each mouse (n¼ 12) was measured at five time points: baseline (during the procedure before regional hemorrhage induction) and 3, 12, 24, and 48 h post-hemorrhage. At each time point, the animal was placed under the microscope, and images were taken through the cranial windows after the mice were
Table 2 – Methodologic differences between the present study and that of Britz et al. (2007)
Animals Model Anesthetic PaCO2 before/after CO2 inhalation Concentration of CO2 inhaled Duration of CO2 inhalation
The present study
The study of Britz et al.
Mice Regional hemorrhage in subarachnoid space with rupture of pial arteriole α-chloralose(80 mg/kg, i.p.) 29.771.0/58.973.4
Rats Endovascular filament model of subarachnoid hemorrhage α-chloralose þurethane(50 and 500 mg/kg, respectively, i.p.) 32.9.273.7/46.276.1
5% CO2/30% O2
6% CO2/34% O2
5 min
2 min
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anesthetized with α-chloralose (80 mg/kg, intraperitoneally [i. p.], Sigma-Aldrich, St. Louis, MO, USA). The second set of experiments was designed to explore the vasoreactivity to hypercapnia, ACh, and SNAP after hemorrhage. Two groups of mice were used: a shamoperated group (n¼ 6) and a hemorrhage group (n ¼6). In both groups, vasoreactivity (the vascular response to vasoactive stimuli) was tested at 24 h after cranial window implantation.
4.4.
Vasoreactivity to hypercapnia
The responses of the vessels to hypercapnia were detected to assess the ability of vascular regulation after hemorrhage. The mice were anesthetized with isoflurane (Hospira, Lake Forest, IL, USA) and α-chloralose (80 mg/kg, i.p.) and ventilated at a stroke volume of 5 ml/kg body weight and ventilation rate of 150 strokes/min with a rodent ventilator (Harvard Apparatus Co., Holliston, MA, USA). Body temperature was maintained at 37 1C using a heating pad (Harvard Apparatus Co.). An arterial catheter was placed into the femoral artery for measurement of the mean arterial blood pressure (MBP) and blood gases. The isoflurane was reduced gradually to zero before the mouse was placed under the microscope. After an equilibration period, an image of the region with a clear pial arteriole (15–20 μm in diameter) without injury and located in the region of bleeding was taken for comparison to baseline conditions while the animals were ventilated with 30% O2-containing air. Subsequently, changes in PaCO2 were induced by ventilating the animal with 5% CO2/30% O2containing air for 5 min. Blood gases were analyzed before hypercapnia, 4 min after hypercapnia, and 4 min after recovery. Images were taken through the cranial windows after completion of hypecapnia.
4.5.
Vasoreactivity to ACh
The endothelium-dependent vasodilator ACh (100 μM; SigmaAldrich) was infused into the cranial window at a rate of 20 μl/min for 5 min after the baseline image was taken. Upon completion of Ach infusion, another image was taken through the cranial window, and artificial cerebrospinal fluid was then infused for 10–20 min or until the vessel diameter returned to its baseline value.
4.6.
Vasoreactivity to SNAP
The vascular SMC-dependent vasodilator SNAP (500 μM; SigmaAldrich) was infused into the cranial window at a rate of 20 μl/min for 5 min after the baseline image was taken. Upon completion of SNAP infusion, another image was taken through the cranial window, and artificial cerebrospinal fluid was then infused for 10–20 min or until the vessel diameter returned to its baseline value. The order of vasodilatory agent treatment was randomly assigned.
4.7.
Vessel diameter measurement
Vessel diameter was determined using Diamtrak software (Tim Neild, Monash University, Melbourne, Australia) as described previously (Han et al., 2008). Briefly, averaged vessel
diameters across a 25-μm longitudinal segment (at least four consecutive segments were measured per artery) of the vessels of interest were analyzed before (baseline) and after exposure to hypercapnia, Ach, or SNAP. The vasoreactivity was calculated as the percent (%) vasodilation relative to the baseline vessel diameter.
4.8.
Statistical analysis
Data are expressed as means7standard error of the mean (SEM). Comparisons among multiple groups were performed by one-way analysis of variance followed by the Dunnett's multiple comparison method. P values o0.05 were considered significant.
Sources of funding This work was supported by grants from the National Natural Science Foundation of China (NSFC): No. 81000503(ML Zhou).
Conflict(s)-of-interest/Disclosure(s) none
r e f e r e n c e s
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