Editorial Collateral Development The Quest Continues Nicole L. Lohr
T
he promise of stimulating collateral blood vessel growth in the heart, brain, or peripheral circulation remains a holy grail in the field of vascular biology. For decades, clinicians and researchers have observed some individuals remain asymptomatic, despite highly obstructive atherosclerotic disease because they possess well-developed innate collateral vessels.1–4 To date, we stand on a mountain of evidence supporting their existence, their potential to be modified by various stimuli (eg, shear stress and ischemia), and their clinical benefits.5–7 Yet, we incompletely understand how much of collateral development depends on the genetic composition of a patient, and how much it is related to the environment in which these vessels are exposed.
Article, see p 660 A functional collateral circulation is the end result of 2 different processes: collaterogenesis and arteriogenesis. During embryogenesis, arterial–arterial connections at the level of the microcirculation form within the heart, brain, and skeletal muscle. In the brain, this mechanism occurs through the direct sprouting and proliferation of endothelial cells to form tubes that directly attach to a neighboring arteriole.8 Vascular endothelial growth factor (VEGF) seems to mediate this endothelial migration and proliferation through its receptor, flk-1, and Notch signal pathway.9 VEGF levels were directly related to the extent of native collateral growth in the brain and skeletal muscles when measured in different mouse strains.10,11 Interestingly, an expression quantitative trait locus (QTL) on chromosome 17 near vegfa was identified as a possible cause for the strain-dependent variation in VEGF expression.11 This first phase of collateral development is the establishment of arterial connections; however, these vessels are incapable of conducting sufficient blood flow to meet the tissue’s metabolic needs. The postnatal remodeling of pre-existing arteriolar anastomoses is the hallmark of arteriogenesis. In the heart, arterial– arterial anastomoses (20–200-μm diameter) are incapable of conducting sufficient blood flow to support cellular metabolism because of their small caliber and lack of muscularity.5,7,12 Environmental stimuli, such as changes in physical forces (eg,
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; and the Department of Medicine, Clement J Zablocki VA Medical Center, Milwaukee, WI. Correspondence to Nicole L. Lohr, MD, PhD, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail [email protected] (Circ Res. 2014;114:591-593.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.303402
shear stress) or ischemia because of vascular occlusion from atherosclerotic disease, lead to increased growth factor expression.13,14 The endothelium, in response to these stimuli, recruits immune cells and endothelial progenitor cells, which secrete more growth factors to stimulate smooth muscle cell recruitment.5 Moreover, genotype analysis from patients with acute and chronic coronary disease identified significant association between VEGF mutations and collateral size.15 Within the VEGF signaling pathway, a glu298arg allele within the endothelial nitric oxide synthase gene leads to its impaired expression and poor collateral remodeling.16 Alleles for hypoxia-inducible factor-1α, a transcription factor capable of inducing VEGF, have been associated with collateral development.17,18 These results highlight the complexity of vascular remodeling and the multiple layers of regulation, genetic, and environmental, which are necessary in this process. In this issue of Circulation Research, Sealock et al19 further our understanding of the genetic basis of collateralization in the brain and peripheral circulation through congenic mapping of a 27 Mb region on mouse chromosome 7 (Candq1) attributed to strain-dependent differences in innate collateral vessel diameter and number. Candq1 is located within a region containing other QTLs (Civq-5, Lsq-1) associated with differences in hindlimb perfusion and cerebral infarct volumes but does not share candidate gene targets with these loci.19 This divergence identified a need to refine and reconcile QTLs identified indirectly by ischemia with those identified by structural characteristics to the same physiological process (ie, collateralization). Congenic lines were developed by introgressing sections of Candq1 from c57bl/6 mice, a collateral-rich strain, to the background of BalbC, a collateral-poor strain. Phenotypic analysis, by measuring native collateral number, vessel size, infarct volume, and femoral blood flow, resulted in the direct characterization of a candidate region to 737 kb and included 28 genes. These candidate genes do not overlap with those in the previous identified QTLs. Because endothelial cell sprouting is required for collaterogenesis, first-line candidates were directed toward endothelial cell expressing genes. In silico analysis of single nucleotide polymorphisms and miRNA targets within the Dce-1 QTL highlighted a membrane trafficking protein rabep2 as the potential master controller of collaterogenesis. What makes Rabep2 an intriguing candidate for control of collaterogenesis is that it crosses paths with VEGF signaling. The VEGF receptor, KDR/flk-1, is responsible for mediating VEGF-stimulated proliferation and migration in collateral development.20 Rabep2 binds to Rab5 and the Rab5 exchange factor on the endosomal membrane to form the early endosome (Figure).21–23 In vitro, Rabep2 is necessary for the activation of Rab5, thus Rabep2 has the potential to regulate collateral development through endocytic trafficking of the activated
Downloaded from http://circres.ahajournals.org/ 591 at UNIV OF MASSACHUSETTS on April 7, 2015
592 Circulation Research February 14, 2014
Figure. Proposed role of Rabep2 in vascular endothelial growth factor (VEGF)–mediated collaterogenesis. The activation of the VEGF receptor 2 leads to signal activation and rapid internalization. Rab trafficking proteins are in the cytosol and travel to the endosomal membrane after release of its respective GDP dissociation inhibitor (GDI). Rab guanine exchange factor (GEF) activates Rab5 by replacing its GDP with GTP. Rab5 can now bind effector molecules, such as Rabep2. These proteins, in conjunction with internalized VEGF receptor 2, form the early endosome, and VEGF signaling is attenuated.
VEGF receptor KDR/flk-1.24 Whether this is the master controller of native collateral development remains to be seen because genetic knockouts are in the process of development. Previous genetic studies where the extent of native collateral development was measured in VEGF overexpressing mice indicated the VEGF receptor 1, or flt-1, was a key mediator in the hindlimb, whereas flk-1 did not affect the extent of collaterogenesis.8 In the leptomeningeal collateral circulation, VEGF receptor 2 is found to be critical for collateral extent9 through Notch1 (Figure). This previous finding could conflict with Rabep2 and VEGF receptor trafficking as a mechanism for regulating native collateral growth. It would be interesting to know whether VEGF protein or receptor expression is altered in these congenic lines. There is no obvious gene or miRNA, which could be directly attributed to the observed increases in collateral size and number. This highlights the frequent dilemma presented in genetic-based research. How can the results be interpreted and studied? Some candidates are dismissed because the transgenic knockout did not abolish collateralization (eg, jmjd5). Some candidates have unknown function. Some are expressed outside of the vasculature. This raises the question; can collateral development be defined by the absence of a single gene? I would argue the hypothesis that a single gene is responsible for native collateral extent must be met with skepticism. Collateral development occurs in diverse vascular beds and is subject to varying environmental factors. Phenotyping of the congenic lines used in this study were mainly focused on leptomeningeal collateral formation. This is evidenced by the inability of the introgressed collateral-rich strain to restore collateralization fully in the skeletal muscle of the collateral-poor strain. This may also explain the previous observation that flt-1 receptor signaling is important to hindlimb collateral development. Rabep2 might be the master controller in leptomeningeal collaterals but what about Rabep2’s function in other vascular beds? As a vascular biology community, we continue on our quest to understand collateral development with the hope of 1 day using them as a practical therapy. I think that Sealock et al19
have made a significant advancement by shifting our focus in a promising new direction toward membrane trafficking. I look forward to the next chapter in this collateral saga.
Acknowledgment I thank Dorothee Weihrauch, DVM, PhD for her thoughtful and careful review of this article.
Disclosures None.
References 1. Seiler C, Engler R, Berner L, Stoller M, Meier P, Steck H, Traupe T. Prognostic relevance of coronary collateral function: confounded or causal relationship? Heart. 2013;99:1408–1414. 2. Seiler C. The human coronary collateral circulation. Heart. 2003;89:1352–1357. 3. Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, Lee KH, Liebeskind DS. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Stroke. 2011;42:693–699. 4. Billinger M, Kloos P, Eberli FR, Windecker S, Meier B, Seiler C. Physiologically assessed coronary collateral flow and adverse cardiac ischemic events: a follow-up study in 403 patients with coronary artery disease. J Am Coll Cardiol. 2002;40:1545–1550. 5. Schaper W. Collateral circulation. Basic Res Cardiol. 2009;104:5–21. 6. Scholz D, Ziegelhoeffer T, Helisch A, Wagner S, Friedrich C, Podzuweit T, Schaper W. Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice. J Mol Cell Cardiol. 2002;34:775–787. 7. van Royen N, Piek JJ, Schaper W, Fulton WF. A critical review of clinical arteriogenesis research. J Am Coll Cardiol. 2009;55:17–25. 8. Clayton JA, Chalothorn D, Faber JE. Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ Res. 2008;103:1027–1036. 9. Lucitti JL, Mackey JK, Morrison JC, Haigh JJ, Adams RH, Faber JE. Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17. Circ Res. 2012;111:1539–1550. 10. Chalothorn D, Faber JE. Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics. 2010;42: 469–479. 11. Chalothorn D, Clayton JA, Zhang H, Pomp D, Faber JE. Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains. Physiol Genomics. 2007;30:179–191.
Downloaded from http://circres.ahajournals.org/ at UNIV OF MASSACHUSETTS on April 7, 2015
Lohr Congenic Approach to Collateral Development 593 12. Chilian WM, Penn MS, Pung YF, Dong F, Mayorga M, Ohanyan V, Logan S, Yin L. Coronary collateral growth—back to the future. J Mol Cell Cardiol. 2012;52:905–911. 13. Teunissen PF, Horrevoets AJ, van Royen N. The coronary collateral circulation: genetic and environmental determinants in experimental models and humans. J Mol Cell Cardiol. 2012;52:897–904. 14. Deindl E, Buschmann I, Hoefer IE, Podzuweit T, Boengler K, Vogel S, van Royen N, Fernandez B, Schaper W. Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ Res. 2001;89:779–786. 15. Ripa RS, Jørgensen E, Baldazzi F, Frikke-Schmidt R, Wang Y, Tybjaerg-Hansen A, Kastrup J. The influence of genotype on vascular endothelial growth factor and regulation of myocardial collateral blood flow in patients with acute and chronic coronary heart disease. Scand J Clin Lab Invest. 2009;69:722–728. 16. Lamblin N, Cuilleret FJ, Helbecque N, Dallongeville J, Lablanche JM, Amouyel P, Bauters C, Van Belle E. A common variant of endothelial nitric oxide synthase (Glu298Asp) is associated with collateral development in patients with chronic coronary occlusions. BMC Cardiovasc Disord. 2005;5:27. 17. Resar JR, Roguin A, Voner J, Nasir K, Hennebry TA, Miller JM, Ingersoll R, Kasch LM, Semenza GL. Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart disease. Chest. 2005;128:787–791. 18. Schultz A, Lavie L, Hochberg I, Beyar R, Stone T, Skorecki K, Lavie P, Roguin A, Levy AP. Interindividual heterogeneity in the hypoxic
regulation of VEGF: significance for the development of the coronary artery collateral circulation. Circulation. 1999;100:547–552. 19. Sealock R, Zhang H, Lucitti JL, Moore SM, Faber JE. Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity. Circ Res. 2014;114:660–671. 20. Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N, Ferrara N. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem. 2001;276:3222–3230. 21. Gournier H, Stenmark H, Rybin V, Lippé R, Zerial M. Two distinct effectors of the small GTPase Rab5 cooperate in endocytic membrane fusion. EMBO J. 1998;17:1930–1940. 22. Stenmark H, Vitale G, Ullrich O, Zerial M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995;83:423–432. 23. Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91:119–149. 24. Jopling HM, Odell AF, Hooper NM, Zachary IC, Walker JH, Ponnambalam S. Rab GTPase regulation of VEGFR2 trafficking and signaling in endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29:1119–1124. Key Words: Editorials ■ rab G-proteins
■
cerebral infarction
■
collateral circulation
Downloaded from http://circres.ahajournals.org/ at UNIV OF MASSACHUSETTS on April 7, 2015
Collateral Development: The Quest Continues Nicole L. Lohr Circ Res. 2014;114:591-593 doi: 10.1161/CIRCRESAHA.114.303402 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/4/591
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ at UNIV OF MASSACHUSETTS on April 7, 2015
T
he promise of stimulating collateral blood vessel growth in the heart, brain, or peripheral circulation remains a holy grail in the field of vascular biology. For decades, clinicians and researchers have observed some individuals remain asymptomatic, despite highly obstructive atherosclerotic disease because they possess well-developed innate collateral vessels.1–4 To date, we stand on a mountain of evidence supporting their existence, their potential to be modified by various stimuli (eg, shear stress and ischemia), and their clinical benefits.5–7 Yet, we incompletely understand how much of collateral development depends on the genetic composition of a patient, and how much it is related to the environment in which these vessels are exposed.
Article, see p 660 A functional collateral circulation is the end result of 2 different processes: collaterogenesis and arteriogenesis. During embryogenesis, arterial–arterial connections at the level of the microcirculation form within the heart, brain, and skeletal muscle. In the brain, this mechanism occurs through the direct sprouting and proliferation of endothelial cells to form tubes that directly attach to a neighboring arteriole.8 Vascular endothelial growth factor (VEGF) seems to mediate this endothelial migration and proliferation through its receptor, flk-1, and Notch signal pathway.9 VEGF levels were directly related to the extent of native collateral growth in the brain and skeletal muscles when measured in different mouse strains.10,11 Interestingly, an expression quantitative trait locus (QTL) on chromosome 17 near vegfa was identified as a possible cause for the strain-dependent variation in VEGF expression.11 This first phase of collateral development is the establishment of arterial connections; however, these vessels are incapable of conducting sufficient blood flow to meet the tissue’s metabolic needs. The postnatal remodeling of pre-existing arteriolar anastomoses is the hallmark of arteriogenesis. In the heart, arterial– arterial anastomoses (20–200-μm diameter) are incapable of conducting sufficient blood flow to support cellular metabolism because of their small caliber and lack of muscularity.5,7,12 Environmental stimuli, such as changes in physical forces (eg,
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; and the Department of Medicine, Clement J Zablocki VA Medical Center, Milwaukee, WI. Correspondence to Nicole L. Lohr, MD, PhD, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail [email protected] (Circ Res. 2014;114:591-593.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.303402
shear stress) or ischemia because of vascular occlusion from atherosclerotic disease, lead to increased growth factor expression.13,14 The endothelium, in response to these stimuli, recruits immune cells and endothelial progenitor cells, which secrete more growth factors to stimulate smooth muscle cell recruitment.5 Moreover, genotype analysis from patients with acute and chronic coronary disease identified significant association between VEGF mutations and collateral size.15 Within the VEGF signaling pathway, a glu298arg allele within the endothelial nitric oxide synthase gene leads to its impaired expression and poor collateral remodeling.16 Alleles for hypoxia-inducible factor-1α, a transcription factor capable of inducing VEGF, have been associated with collateral development.17,18 These results highlight the complexity of vascular remodeling and the multiple layers of regulation, genetic, and environmental, which are necessary in this process. In this issue of Circulation Research, Sealock et al19 further our understanding of the genetic basis of collateralization in the brain and peripheral circulation through congenic mapping of a 27 Mb region on mouse chromosome 7 (Candq1) attributed to strain-dependent differences in innate collateral vessel diameter and number. Candq1 is located within a region containing other QTLs (Civq-5, Lsq-1) associated with differences in hindlimb perfusion and cerebral infarct volumes but does not share candidate gene targets with these loci.19 This divergence identified a need to refine and reconcile QTLs identified indirectly by ischemia with those identified by structural characteristics to the same physiological process (ie, collateralization). Congenic lines were developed by introgressing sections of Candq1 from c57bl/6 mice, a collateral-rich strain, to the background of BalbC, a collateral-poor strain. Phenotypic analysis, by measuring native collateral number, vessel size, infarct volume, and femoral blood flow, resulted in the direct characterization of a candidate region to 737 kb and included 28 genes. These candidate genes do not overlap with those in the previous identified QTLs. Because endothelial cell sprouting is required for collaterogenesis, first-line candidates were directed toward endothelial cell expressing genes. In silico analysis of single nucleotide polymorphisms and miRNA targets within the Dce-1 QTL highlighted a membrane trafficking protein rabep2 as the potential master controller of collaterogenesis. What makes Rabep2 an intriguing candidate for control of collaterogenesis is that it crosses paths with VEGF signaling. The VEGF receptor, KDR/flk-1, is responsible for mediating VEGF-stimulated proliferation and migration in collateral development.20 Rabep2 binds to Rab5 and the Rab5 exchange factor on the endosomal membrane to form the early endosome (Figure).21–23 In vitro, Rabep2 is necessary for the activation of Rab5, thus Rabep2 has the potential to regulate collateral development through endocytic trafficking of the activated
Downloaded from http://circres.ahajournals.org/ 591 at UNIV OF MASSACHUSETTS on April 7, 2015
592 Circulation Research February 14, 2014
Figure. Proposed role of Rabep2 in vascular endothelial growth factor (VEGF)–mediated collaterogenesis. The activation of the VEGF receptor 2 leads to signal activation and rapid internalization. Rab trafficking proteins are in the cytosol and travel to the endosomal membrane after release of its respective GDP dissociation inhibitor (GDI). Rab guanine exchange factor (GEF) activates Rab5 by replacing its GDP with GTP. Rab5 can now bind effector molecules, such as Rabep2. These proteins, in conjunction with internalized VEGF receptor 2, form the early endosome, and VEGF signaling is attenuated.
VEGF receptor KDR/flk-1.24 Whether this is the master controller of native collateral development remains to be seen because genetic knockouts are in the process of development. Previous genetic studies where the extent of native collateral development was measured in VEGF overexpressing mice indicated the VEGF receptor 1, or flt-1, was a key mediator in the hindlimb, whereas flk-1 did not affect the extent of collaterogenesis.8 In the leptomeningeal collateral circulation, VEGF receptor 2 is found to be critical for collateral extent9 through Notch1 (Figure). This previous finding could conflict with Rabep2 and VEGF receptor trafficking as a mechanism for regulating native collateral growth. It would be interesting to know whether VEGF protein or receptor expression is altered in these congenic lines. There is no obvious gene or miRNA, which could be directly attributed to the observed increases in collateral size and number. This highlights the frequent dilemma presented in genetic-based research. How can the results be interpreted and studied? Some candidates are dismissed because the transgenic knockout did not abolish collateralization (eg, jmjd5). Some candidates have unknown function. Some are expressed outside of the vasculature. This raises the question; can collateral development be defined by the absence of a single gene? I would argue the hypothesis that a single gene is responsible for native collateral extent must be met with skepticism. Collateral development occurs in diverse vascular beds and is subject to varying environmental factors. Phenotyping of the congenic lines used in this study were mainly focused on leptomeningeal collateral formation. This is evidenced by the inability of the introgressed collateral-rich strain to restore collateralization fully in the skeletal muscle of the collateral-poor strain. This may also explain the previous observation that flt-1 receptor signaling is important to hindlimb collateral development. Rabep2 might be the master controller in leptomeningeal collaterals but what about Rabep2’s function in other vascular beds? As a vascular biology community, we continue on our quest to understand collateral development with the hope of 1 day using them as a practical therapy. I think that Sealock et al19
have made a significant advancement by shifting our focus in a promising new direction toward membrane trafficking. I look forward to the next chapter in this collateral saga.
Acknowledgment I thank Dorothee Weihrauch, DVM, PhD for her thoughtful and careful review of this article.
Disclosures None.
References 1. Seiler C, Engler R, Berner L, Stoller M, Meier P, Steck H, Traupe T. Prognostic relevance of coronary collateral function: confounded or causal relationship? Heart. 2013;99:1408–1414. 2. Seiler C. The human coronary collateral circulation. Heart. 2003;89:1352–1357. 3. Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, Lee KH, Liebeskind DS. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Stroke. 2011;42:693–699. 4. Billinger M, Kloos P, Eberli FR, Windecker S, Meier B, Seiler C. Physiologically assessed coronary collateral flow and adverse cardiac ischemic events: a follow-up study in 403 patients with coronary artery disease. J Am Coll Cardiol. 2002;40:1545–1550. 5. Schaper W. Collateral circulation. Basic Res Cardiol. 2009;104:5–21. 6. Scholz D, Ziegelhoeffer T, Helisch A, Wagner S, Friedrich C, Podzuweit T, Schaper W. Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice. J Mol Cell Cardiol. 2002;34:775–787. 7. van Royen N, Piek JJ, Schaper W, Fulton WF. A critical review of clinical arteriogenesis research. J Am Coll Cardiol. 2009;55:17–25. 8. Clayton JA, Chalothorn D, Faber JE. Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ Res. 2008;103:1027–1036. 9. Lucitti JL, Mackey JK, Morrison JC, Haigh JJ, Adams RH, Faber JE. Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17. Circ Res. 2012;111:1539–1550. 10. Chalothorn D, Faber JE. Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics. 2010;42: 469–479. 11. Chalothorn D, Clayton JA, Zhang H, Pomp D, Faber JE. Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains. Physiol Genomics. 2007;30:179–191.
Downloaded from http://circres.ahajournals.org/ at UNIV OF MASSACHUSETTS on April 7, 2015
Lohr Congenic Approach to Collateral Development 593 12. Chilian WM, Penn MS, Pung YF, Dong F, Mayorga M, Ohanyan V, Logan S, Yin L. Coronary collateral growth—back to the future. J Mol Cell Cardiol. 2012;52:905–911. 13. Teunissen PF, Horrevoets AJ, van Royen N. The coronary collateral circulation: genetic and environmental determinants in experimental models and humans. J Mol Cell Cardiol. 2012;52:897–904. 14. Deindl E, Buschmann I, Hoefer IE, Podzuweit T, Boengler K, Vogel S, van Royen N, Fernandez B, Schaper W. Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ Res. 2001;89:779–786. 15. Ripa RS, Jørgensen E, Baldazzi F, Frikke-Schmidt R, Wang Y, Tybjaerg-Hansen A, Kastrup J. The influence of genotype on vascular endothelial growth factor and regulation of myocardial collateral blood flow in patients with acute and chronic coronary heart disease. Scand J Clin Lab Invest. 2009;69:722–728. 16. Lamblin N, Cuilleret FJ, Helbecque N, Dallongeville J, Lablanche JM, Amouyel P, Bauters C, Van Belle E. A common variant of endothelial nitric oxide synthase (Glu298Asp) is associated with collateral development in patients with chronic coronary occlusions. BMC Cardiovasc Disord. 2005;5:27. 17. Resar JR, Roguin A, Voner J, Nasir K, Hennebry TA, Miller JM, Ingersoll R, Kasch LM, Semenza GL. Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart disease. Chest. 2005;128:787–791. 18. Schultz A, Lavie L, Hochberg I, Beyar R, Stone T, Skorecki K, Lavie P, Roguin A, Levy AP. Interindividual heterogeneity in the hypoxic
regulation of VEGF: significance for the development of the coronary artery collateral circulation. Circulation. 1999;100:547–552. 19. Sealock R, Zhang H, Lucitti JL, Moore SM, Faber JE. Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity. Circ Res. 2014;114:660–671. 20. Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N, Ferrara N. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem. 2001;276:3222–3230. 21. Gournier H, Stenmark H, Rybin V, Lippé R, Zerial M. Two distinct effectors of the small GTPase Rab5 cooperate in endocytic membrane fusion. EMBO J. 1998;17:1930–1940. 22. Stenmark H, Vitale G, Ullrich O, Zerial M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995;83:423–432. 23. Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91:119–149. 24. Jopling HM, Odell AF, Hooper NM, Zachary IC, Walker JH, Ponnambalam S. Rab GTPase regulation of VEGFR2 trafficking and signaling in endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29:1119–1124. Key Words: Editorials ■ rab G-proteins
■
cerebral infarction
■
collateral circulation
Downloaded from http://circres.ahajournals.org/ at UNIV OF MASSACHUSETTS on April 7, 2015
Collateral Development: The Quest Continues Nicole L. Lohr Circ Res. 2014;114:591-593 doi: 10.1161/CIRCRESAHA.114.303402 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/4/591
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ at UNIV OF MASSACHUSETTS on April 7, 2015
