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Annu. Rev. Phy.iol. 1990. 52:661-74 Copyright © 1990 by Annual Reviews Inc. All rights reserved

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STIMULUS-SECRETION COUPLING IN VASCULAR ENDOTHELIAL CELLS Andrew C. Newby and Andrew H. Henderson Department of Cardiology, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, Wales, UK

KEY WORDS:

vasodilatation, calcium, prostaglandins, thrombosis, growth factors

INTRODUCTION: SECRETORY FUNCTIONS OF ENDOTHELIUM Endothelium contributes to regulation of vasomotor tone through secretion of two well-characterized vasodilator substances, prostacyclin and endothelium­ derived relaxing factor (EDRF). Endothelial cells may also secrete the en­ dothelium-dependent vasodilators ATP, acety lc holine, and substance P, and at least one peptide vasoconstrictor substance, endothelin. Endothelium­ derived vasoactive agents may be important in mediating the influence of flow on vasomotor tone, vascular geometry, and angiogenesis (35). A second function of endothelium is regulation of intravascular thrombosis. This may be promoted by secretion of platelet adhesion proteins including thrombospondin, fibronectin, collagen, and von Willebrand factor (VWF), but prevented by the secretion of prostacyclin and EDRF, which inhibit platelet activation synergistically.Endothelium promotes coagulation through expression of tissue factor and secretion of factor V, and plasminogen activa­ tor inhibitor (PAl), but inhibits coagUlation through secretion of thrombomod­ ulin and tissue plasminogen activator (TPA). Endothelial secretion of mitogens and growth inhibitors for vascular smooth muscle may be important in atherogenesis. Endothelial regulation of the extravasation of leucocytes by expressi on of adhesion proteins and secre -

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tion of interleukin- l (IL- l ) and platelet activating factor (PAF) (21) is also r�levant to atherogenesis and to the inflammatory response. In this review, we concentrate on the regulation rather than the biochemical mechanisms of secretion. Our limited discussion cannot take into account the extensive and important functional diversity of endothelium through the vascular tree. The selection of agents for more detailed description is likewise not comprehensive, but is chosen to illustrate principles and experimental approaches.

SECOND-MESSENGER PATHWAYS P hosphoinositidase FORMATION OF INOSITOL PHOSPHATES AND DIACYLGLYCEROL In many cell-types, activation of a phosphatidylinositol-specific phospholipase C ("phosphoinositidase") hydrolyses phosphatidylinositol 4,5-bisphosphate to yield the intracellular second-messengers inositol 1,4, 5-trisphosphate [ins­ (1,4,5)P31 and diacylglycerol (4). A guanyl nucleotide transducing protein couples receptors to activation of phosphoinositidase, and in some cases this step is sensitive to inhibition by pertussis toxin (4). Once formed, ins­ (1,4,5)P3 causes mobilization of calcium from endoplasmic reticular in­ tracellular stores, and diacylglycerol activates protein kinase C (4)-an action mimicked by tumor promoting phorbol esters. In endothelial cells, prompt formation of ins(1, 4,5)P3 occurs in response to ADP and ATP (P2y receptor) (29, 79), bradykinin (B2 receptor) (24, 51), endothelial cell growth factor (72), histamine (HI receptor) (58, 80, 83), thrombin (39, 71, 80), and mellitin, a direct activator of phosphoinositidase (59). A simultaneous decrease in phosphatidylinositoI4,5-bisphosphate (51) and an increase in diacylglycerol (71) have also been documented, albeit not as widely. Evidence that diacylglycerol may activate protein kinase C can be inferred from the actions of phorbol esters on endothelial cells (20, 22, 23, 56). Formation of ins(1,4,5)P3 does not depend on elevation of intracellular calcium or on the presence of extracellular calcium (39), but probably in­ volves a guanyl nucleotide transducing protein, since formation of ins­ (l,4,5)P3 in response to ATP (78) (although not bradykinin, 51) is inhibited by pertussis toxin. Other phosphoinositide metabolites are also formed after agonist stimula­ tion of endothelial cells. Inositol 4,5-bisphosphate is formed as rapidly as ins(1,4,5)P3 while inositol monophosphate isomers and glycerophosphoryl­ inositol are formed more slowly (24, 51, 71, 72, 80, 83). Inositol 1,3,4,5tetrakisphosphate is also formed slowly (80), consistent with the presence of an active ins(I,4,5)Pr3-kinase (71, 80), possibly activated by elevation of intracellular calcium (72). Rapid formation of its degradative product, inosi-

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tol 1,3,4-trisphosphate, does not occur, however, in stimulated human or pig endothelial cells (71, 80), although it is the major isomer in unstimulated cells (80). Endothelial cytoplasmic calcium concentration is elevated by acetylcholine (9), ADP or ATP (P2y receptor) (38,79), bradykinin (B2 receptor) (12, 59,70), histamine (HI receptor) (41, 46, 51, 80, 85), PAF (8), or thrombin (39, 41, 47, 80). This list contains all those agents known to promote endothelial ins(1,4,5)P3 formation, which, in addition, is sufficiently rapid to cxplain the time-course of calcium elevation. Maximal concentrations of agonists typically raise intracellular calcium with­ in seconds from about 0. 1 fLM to above 1 fLM. Calcium concentration then declines rapidly to a lower value before returning more slowly to the resting level. The initial agonist-stimulated rise of calcium concentration is scarcely altered by removal of extracellular calcium, which suggests that it results from mobilization of intracellular stores (9a, 12, 38, 39, 41, 46, 70, 80, 85). The sustained phase of calcium elevation, by contrast, is abolished by remov­ al of extracellular calcium or by addition of inorganic calcium antagonists such as C02+ and Mn2+, which strongly suggests that this phase results from calcium influx (9a,38,41,70, 80, 85). The mechanism of agonist-stimulated calcium influx is uncertain. It might be mediated by ins(1,4,5)P3 alone or together with its metabolite inositol 1,3,4,5-tetrakisphosphate (40). In other cells, however, calcium entry can be distinguished electrophysiologically, kinetically, and pharmacologically from calcium mobilization and hence from ins(1,4,5)P3 formation (40, 69). In single endothelial cells, histamine causes spikes of calcium elevation to almost 1 JLM and of about 30 s duration (46), the frequency but not the magnitude of which increases with agonist concentration (46). In the absence of extracellular calcium, the spikes become progressively smaller and less frequent, apparently ceasing before the intracellular pool is depleted (46). This suggests that repletion of the intracellular pool to a critical level may be necessary before it can be discharged. It is unclear whether this repletion occurs via the cytoplasm or directly from the extracellular space (46). Calcium elevation may be terminated by receptor desensitization (47) or feed-back inhibition of phosphoinositidase by activation of protein kinase C (4).

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ELEVATION OF CYTOSOLIC CALCIUM

Ion Channels Functional and electrophysiologic studies of voltage­ sensitive calcium channels with organic agonists or antagonists have provided evidence for (15, 86, 90) and against (5, 12, 68, 93, 100) their presence in

CALCIUM CHANNELS

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endothelial cells. Depolarization with extracellular potassium does not elevate intracellular calcium concentration (12, 38, 46, 85), and electrophysiologic studies have uniformly failed to detect L-type calcium channels in freshly isolated (9, 75) or cultured (12, 52, 74, 93) endothelial cells. A stretch­ activated single channel conductance with a modest sixfold preference for calcium over sodium has been detected in pig aortic endothelial cells (52), which suggests that it might be responsible for significant entry of calcium in response to increased shear force (5, 73). Annu. Rev. Physiol. 1990.52:661-674. Downloaded from www.annualreviews.org Access provided by University of British Columbia on 02/04/15. For personal use only.



POTASSIUM CHANNELS Endothelial cells exposed to steady shear (5, 73, 74) or to acetylcholine (9, 74, 75), bradykinin (12), leucotrieneB4 (LTB4) (53), or PAF (53) undergo membrane hyperpolarization. Shear-activated and acetylcholine-operated potassium channels may mediate hyperpolarization directly (74, 75). Hyperpolarization may also occur secondarily to elevation of intracellular calcium concentration (5) via a calcium-activated potassium channel (9, 12). CALCIUM/SODIUM AND SODIuM/PROTON EXCHANGE ADP, ATP (Pz puri­ noreceptor), or the calcium ionophore A23l 87 causes transient acidification and sustained alkalinization of the cytoplasm of bovine aortic endothelial cells (50). The pH changes depend on the extracellular calcium, sodium, and proton concentrations and are inhibited by amiloride (50), which suggests that they involve sequential calcium/sodium and sodiUm/proton exchange. Adenylate and Guanylate Cyclases Endothelial cells contain an adenyl ate cyclase that is activated by prostaglan­ dins of the E and I series (2, 48, 99), �-adrenergic agonists (48), and the direct activator forskolin (48, 66, 99). Inhibition of the adenylate cyclase by a-adrenergic agonists has also been reported (48). Endothelial cells contain soluble guanylate cyclase that is activated by NO, N3, nitroprusside, tert-butylhydroperoxide, and glyceryltrinitrate and particu­ late guanylate cyclase that is activated by atriopeptins (1, 66). In some cell types cyclic nucleotides modulate the activity of the phos­ phoinositidase pathway (4). In endothelial cells, however, cAMP elevation may not inhibit formation of ins(1,4,5)P3 (78), and the effect of cGMP elevation on phosphoinositidase has not been studied directly.

EXAMPLES OF STIMULUS-SECRETION COUPLING MECHANISMS Prostaglandins Endothelial cells metabolize arachidonate mainly to prostacyc1in and pro­ staglandin Ez (26, 81, 83, 84, 99) with smaller amounts of thromboxane Az

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(TXA2) (26, 83). Secretion of prostaglandins occurs spontaneously and in response to increased shear force (5). It is also rapidly stimulated by ATP (20), bradykinin (B2 receptor) (1, 11, 15, 20, 24, 44, 62, 84, 98, 99), histamine (HI receptor) (1, 83, 84), and thrombin (1, 2, 39, 47, 81, 84, 99), all of which increase endothelial intracellular calcium, and also by the cal­ cium ionophores A23187 and ionomycin (1, 2, 11, 22, 78, 81, 84, 98, 99). The agonist-stimulated formation of ins( l , 4,5)P3 and increase in intracellular calcium precede the initial stimulation of prostaglandin formation (24, 39, 62, 83). The r �te of prostaglandin formation, however, then declines before intracellular calcium returns to resting levels (39, 62), which suggests that there may be a threshold intracellular calcium concentration (for example, 0. 8 JLM in human umbilical vein endothelial cells, 39) for stimulation of prosta­ glandin formation. Evidence for a calcium threshhold also comes from correlation of prostaglandin formation with the peak intracellular calcium response to different concentrations of agonist (ATP) or calcium ionophore (9a). Agonist-stimulated prostaglandin formation is only slightly inhibited by removal of extracellular calcium (1, 39, 62, 99), but it may be abolished by depletion of the intracellular calcium store (39). Such depletion of calcium does not affect formation of ins(I,4, 5)P3, therefore implying that calcium elevation is the essential consequence of receptor-stimulation that mediates prostaglandin formation. In further support of this, prostacyclin production may be inhibited by buffering of intracellular calcium concentration with quin-2 (5). It is also inhibited by TMB-8 (2, 62, 90, 97, but not 5), a supposed inhibitor of intracellular calcium mobilization, although this mechanism of action has been questioned (91). The effects on prostaglandin formation of possible inhibitors of phos­ phoinositidase have also been investigated. These include direct inhibitors such as gentamycin and pertussis toxin and activators of protein kinase C (i.e. phorbol esters), which might cause feed-back inhibition (4). Gentamycin inhibits prostaglandin formation in bovine aortic endothelial cells (20) while pertussis toxin inhibits the response to LTC4 and LTD4 (11), but has no effect on the response to bradykinin (11). In the same cell-type, pertussis toxin potentiates prostaglandin release in response to ATP (and A23187), but partially inhibits ATP-stimulated ins(I,4, 5)P3 formation (78). These data suggest the participation of a second guanyl nucleotide transducing protein in regulation of prostaglandin formation (78). Phorbol 12-myristate 13-acetate (PMA) and R59022 (a diacylglyceride kinase inhibitor that may increase the concentration of endogenous diacylglyceride) also inhibit prostacyc1in release from endothelial cells (9b, 20). However PMA alone can stimulate prosta­ glandin formation in endothelial cells (9b, 22) and acts synergistically with A23187, which suggests that it lowers the calcium threshold for prostaglandin production (9b). PMA might then, as in other cell-types (4), potentiate the effects of calcium elevation while reducing agonist-activated calcium

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mobilization by negative feed-back, thereby preserving the response while avoiding prolonged calcium elevation. There is evidence in endothelial cells for both the phospholipase A2 (and perhaps phospholipase AI. 64) and phospholipase C/diacylglycerol lipase pathways (5, 44, 64, 81, 83) of prostaglandin formation. How these pathways are regulated by calcium is not clear, however. Elevation of endothelial cell cAMP concentration with forskolin or addition of dibutyryl- or 8-bromo-cAMP had no effect on prostaglandin production in two studies (78, 98), but was inhibitory in one other (60). The cAMP phosphodiesterase inhibitor, isobutylmethylxanthine, and the inhibitor of soluble guanylate cyclase, methylene blue, inhibit prostaglandin formation (2, 65), but apparently by direct effects (65, 98). Elevation of endothelial cell cGMP concentration with atriopeptins, organic or inorganic nitrates, also did not inhibit prostaglandin production in four studies (1, 17, 18,65) although a high concentration of NO was effective in one other (25). A slow stimulation of prostacyclin production also occurs in endothelial cells in response to IL-l (21) and tumor necrosis factor (TNF) (10). This takes place over a time-course of minutes or hours; it depends on both RNA and protein synthesis, and it may be mediated by induction of phospholipase A2 (10). The mechanism of stimulus-secretion coupling has not been defined. Endothelium-Derived Relaxing Factor (EDRF)

Chemical assays for EDRF have only recently become available since its identification as nitric oxide (45, 76). Most studies to date have therefore measuredEDRF activity by bioassays (3, 35, 96). Secretion ofEDRF occurs spontaneously and is accelerated by increased shear force (3, 35, 96). Its formation can also be stimulated by acetyl choline, ADP, ATP, bradykinin, histamine, 5-hydroxytryptamine, PAF, substance P, thrombin (a list which again includes all those agents that have been shown to increase endothelial intracellular calcium), and also by the calcium ionophore A23187 (3, 35, 96). Removal of extracellular calcium inhibits both spontaneous (61, 68, 97) and agonist-stimulated (34, 61, 68, 97) EDRF formation although, in some preparations, a transient stimulation ofEDRF formation may still occur (59, 94, 97). Taken together, these data suggest that cytosolic calcium mediates stimulation ofEDRF production. Stimulation ofEDRF production by mellitin (59) and inhibition by phorbol esters (20, 56) further suggest that phosphoino­ sitidase is involved. Control of EDRF and prostaglandin production have been compared in the same cell preparations (62, 97). Stimulation ofEDRF formation appears to be more sustained, which suggests that it continues during the lower plateau phase of calcium elevation and may thus have a lower calcium threshold. An alternative explanation is that EDRF production may be relatively more

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dependent,on·caicium derived from extracellular entry and that prostaglandin production may be more dependent on calcium from intracellular stores. Consistent with this, removal of extracellular calcium causes a greater inhibi­ tion of EDRF production whereas TMB-8, the supposed inhibitor of in­ tracellular calcium mobilization, inhibits prostaglandin but notEDRF produc­ tion. By contrast, elevation of cGMP concentration inhibits EDRF but not prostaglandin formation (28, 43). Since cGMP elevation may have a selective inhibitory effect on calcium entry, at least in platelets (69), inhibition by cGMP might further implicate calcium entry inEDRF production. Inhibition ofEDRF production by an inhibitor of the sodium/hydrogen exchanger (100) suggests that (calcium-dependent) pH changes may also be involved. The initial step in EDRF formation probably involves the metabolism of arginine to citrulline (77). The enzyme likely to be responsible has a divalent cation requirement (77),but whether this accounts for the calcium-activation ofEDRF release is not yet clear. The dependence of stimulated (34) but not spontaneous (33) EDRF formation on mitochodrial ATP generation also remains to be explained.

Proteins and Growth Factors Spontaneous secretion of von Willebrand fac­ tor (VWF) is dependent on protein synthesis (60),as is the case for the other adhesion proteins,fibronectin and thrombospondin (82), thus implying that newly synthesized material is secreted directly. Stimulated secretion, by contrast, is independent of protein synthesis (55, 88) and depletes the cellular content of VWF (in particular that localized in the Weibel-Palade bodies) (82, 88),which implies that it occurs by exocytosis of a stored pool. Secretion may be stimulated by agonists known to cause intracellular calcium elevation, namely thrombin (6,19,41, 55, 60,82),histamine (HI receptor) (41), and epinephrine (6). The calcium ionophore A23187 (19,41,60,82) and PMA 09, 60, 82) are also effectiv e. Buffering of intracellular calcium with quin-2 inhibits secretion stimulated by histamine (41) and removal of extracellular calcium also attenuates responses to thrombin, histamine, and A23187 (but has no effect on spontaneous secretion) (41, 60). By comparison with secre­ tion of prostaglandins, stimulation of VWF secretion is more prolonged (up to 24 hr), more dependent on extracellular calcium, more readily stimulated by VON WILLEBRAND FACTOR

PMA,and less readily inhibited by dibutyryl-cAMP (60). These data suggest

that stimulation of VWF release requires a sustained rise in intracellular calcium andlor activation of protein kinase C. Secretion of VWF is also stimulated by a number of agents not known to cause elevation of intracellular calcium, namely bacterial endotoxin (88), IL-l (6, 88), and

plasmin (6). The stimulus-secretion coupling mechanism

involved has not been elucidated.

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Endothelial cells secrete urokinase-type and tissue-type plasminogen activator (TPA), and a number of plasminogen activator inhibitors, of which PAI-I is the best characterized. TPA is secreted spontaneously and in response to histamine (H I receptor) (54), thrombin (54), and PMA (36, 54). Unlike secretion of prostaglandins, EDRF and VWF, secretion of TPA is not stimulated by A23187 (67) and may therefore involve activation of protein kinase C independently of intracellular calcium elevation. Secretion of TPA requires a lag period of 4-8 hr and is inhibited by IL- l and TNF (87). Secretion of PAL,by contrast,is stimulated by lL-l (21, 27,87, 95), TNF (87, 95), and bacterial endotoxin (14, 27, 95), but not by PMA or A23187 (87, 95), and is accompanied by increased expression of PAl mRNA (87). Stimulation of PAl secretion requires a lag period of 2-12 hr (87, 95), and requires protein synthesis (27). The stimulus-secretion mechanism involved is as yet unknown but appears to be distinct from that for TPA,thereby allowing for their coordinated expression.

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PLASMINOGEN ACTIVATORS AND INHIBITORS

Endothelial cells secrete several peptide mitogens for vascular smooth muscle, among which platelet-derived growth factor A (PDGFA) (13, 49, 57, 92) and PDGFB (17, 49, 57, 92) arc the best characterized, though they may be only minor components of total mitogenic activity (32, 57). Secretion is stimulated by thrombin (16,42, 92),which is known to elevate intracellular calcium, but also by bacterial endotoxin (30), IL-l (37), transforming growth factor-beta (TGF-beta) (17),TNF (37, 92), and PMA (16, 30, 92), which do not elevate calcium. Stimulation leads to two phases of secretion with a first peak at 3-4 hr and a second at 15-17 hr (16,31,37). Secretion may not require either protein or RNA synthesis (31, 42), but neither does it appear to come from a stored precursor pool since endothelial cell lysates contain little growth factor activity (31, 42). This suggests that secretion may involve modification of an inactive, stored pre­ cursor. There may be two independent pathways for stimulus-secretion cou­ pling. PMA, thrombin, and TNF all stimulate secretion of both PDGFA and PDGFB from human microvascular endothelial cells, but PMA is relatively more effective towards PDGFB and TNF towards PDGFA. Moreover, the stimulation by PMA or thrombin is inhibited by forskolin (i.e. cAMP eleva­ tion) whereas stimulation by TNF is not (49, 92). These data suggest that thrombin and PMA may act through one mechanism (most probably activa­ tion of protein kinase C) while TNF acts largely through a distinct but as yet unknown mechanism. Microvascular endothelial cells also secrete hemopoiet­ ic colony stimulating factors (63,89 ), and this also may occur through two independent pathways of stimulus-secretion coupling (89). GROWTH FACTORS

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CONCLUSIONS Intracellular calcium appears to mediate the acute stimulation of endothelial secretion regardless of whether it occurs by synthesis from a precursor as in the case of prostaglandins and EDRF, or by release of a stored pool as in the case of VWF. The evidence for differential secretion of these agents in response to common agonists suggests either the involvement of different pools of intracellular calcium (e.g. derived from entry or intracellular re­ lease), or secondary regulation as for example by protein kinase C or cyclic nucleotide dependent protein kinases; the details of these mechanisms have yet to be elucidated. Protein kinase C may also be involved in the slow activation of TPA secretion and of a component of growth factor secretion, although this is not yet firmly established. Slow stimulation of prostaglandin, PAl, and the remaining component of growth factor secretion can not present­ ly be explained by any second-messenger pathway known to occur in en­ dothelial cells. Further studies of these pathways are particularly warranted. By analogy with activation of other cells, these pathways might possibly involve protein tyrosine kinase activity.

ACKNOWLEDGMENTS A. H. Henderson holds the Sir Thomas Lewis Chair of Cardiology. The authors' work is supported by grants from the British Heart Foundation and the Medical Research Council. Literature Cited 1. Adams Brotherton, A. F. 1986. Induc­ tion of prostacyclin biosynthesis is closely associated with increased guano­ �ine 3' ,S' -cyclic monophosphate accumulation in cultured human en­ dothelium. J. Clin. Invest. 78:1253-60 2. Adams Brotherton, A. F., Hoak, J. C. 1982. Role of Ca2+ and cyclic AMP in the regulation of the production of pro­ stacyclin by the vascular endothelium. Proc. Natl. Acad. Sci. USA 79:495-99 3. Angus, J. A., Cocks, T. M. 1989. En­ dothelium-derived relaxing factor. Phar­ mac. Ther. 41:303-52 4. Berridge, M. J. 1987. Inositol trisphos­ phate and diacylglycerol: two interacting second messengers. Annu. Rev. Bio­ chern. 56:159-93 5. Bhagyalakshmi, A., Frangos, J. A. 1989. Mechanism of shear-induced prostacyclin production in endothelial cells. Biochem. Biophys. Res. Comm. 158:31-37

6. Booth, F., Allington, M. J., Cederholm­ Williams, S. A. 1987. An in vitro model for study of acute release of von Wille­ brand factor from human endothelial cells. Br. J. Haem. 67:71-78 7. Bordet, J.-C., Lagarde, M. 1988. Mod­ ulation of prostacyclin-thromboxane formation by molsidomine during platelet-endothelial cell interactions. Biochem. Pharmacol. 37:3911-14 8. Brock, T. A., Gimbrone, M. A. 1986. Platelet activating factor alters calcium homeostasis in cultured vascular en­ dothelial cells. Am. J. Physiol. 250: H1086-92 9. Busse, R., Fichtner, H., Liickhoff, A., Koh1hardt, M. 1988. Hyperpolarization and increased free calcium in acetylcho­ line-stimulated endothelial cells. Am. J. Physiol. 2SS:H96S-69 9a. Carter, T. D., Hallam, T. J., Cusack, N. J., Pearson, J. D. 1988. Regulation of P2y-purinoreceptor-mediated pros-

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tacyclin release from human endothelial cells by calcium concentration. Br. J. Pharmacol. 95:1181-90 9b. Carter, T. D., Hallam, T. J., Pearson, J. D. 1989. Protein kinase C activation alters the sensitivity of agonist­ stimulated endothelial cell prostacyclin production to intracellular ionized cal­ cium. Biochem. J. 262:431-37 10. Clark, M. A., Chen, M.-J., Crooke, S. T., Bamalaski, J. S. 1988. Tumour ne­ crosis factor (cachetin) induces phospho­ lipase A2 activity and synthesis of a phospholipase Aractivating protein in endothelial cells. Biochem. J. 250:12532 11. Clark, M. A., Conway, T. M., Bennett, e. F., Crooke, S. T., Stadel, J. M. 1986. Islet-activating protein inhibits leukotriene D4- and leukotriene C4- but not bradykinin- or calcium ionophore­ induced prostacyclin synthesis in bovine endothelial cells. Proc. Natl. Acad. Sci. USA 83:7320-24 12. Colden-Standfield, M., Schilling, W. P., Ritchie, A. K., Eskin, S. G., Navar­ ro, L. T., et al. 1987. Bradykinin­ induced increases in cytosolic calcium and ionic currents in cultured bovine aortic endothelial cells. Cir. Res. 61: 632-40 13. Collins, T., Pober, J. S., Gimbrone, M. A., Hammacher, A., Betscholtz, C., et a1. 1987. Cultured human endothelial cells express platelet-derived growth factor A chain. Am. J. Pathol. 127:712 14. Crutchley, D. J., Conanan, L. B., Ryan, U. S. 1987. Endotoxin-induced secre­ tion of an active plasminogen activator inhibitor from bovine pulmonary arterial and aortic endothelial cells. Biochem. Biophys. Res. Comm. 148:1346-53 15. Crutchley, D. J., Ryan, J. W., Ryan, U. S., Fisher, G. H. 1983. Bradykinin­ induced release of prostacyclin and thromboxanes from bovine pulmonary artery endothelial cells. Biochim. Bio­ phys. Acta 751:99-107 16. Daniel, T. 0., Gibbs, V. C., Milfay, D. F., Garovoy, M. R., Williams, L. T. 1986. Thrombin stimulates c-cis gene expression in microvascular endothelial cells. J. Bioi. Chem. 261:9579-82 17. Daniel, T. 0., Gibbs, V. e., Milfay, D. P., Williams, L. T. 1987. Agents that increase cAMP accumulation block en­ dothelial c-cis induction by thrombin and transforming growth factor-(3. J. Bioi. Chem. 262:11893-96 18. De Caterina, R., Dorsol, C. R., Tack­ Goldman, K., Weksler, B. B. 1985. Ni­ trates and endothelial prostacyclin pro-

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