Abstract
Coronary vascular development requires a variety of signaling molecules expressed spatially and temporally, which are activated by metabolic and mechanical factors. Hypoxia plays the earliest role in this activation via its stimulation of hypoxia inducible factor (HIF–1), and the subsequent activation of VEGF and other growth factors. The early growth of the coronary vasculature consists of a tubular network formed prior to myocardial perfusion. A part of this vascular plexus penetrates the aorta, largely in response to VEGF, to form the coronary ostia, which provides the anatomical substrate for coronary flow. Shear stress then becomes a key regulator of the formation of the coronary hierarchy along with the key growth factors that facilitate the formation of the tunica media of the arterial tree, i.e., FGF, PDGF, and TGF-β. Hypoxia plays a dual role by its activation of HIF-1 and by affecting increases in blood flow and shear stress. Growth of the myocardium involves stretch of both cardiomyocytes and blood vessels, which activates stretch signals in both cell types and causes growth factor paracrine and autocrine signaling and consequently, angiogenesis. Shear stress and stretch are the major mechanical influences that drive coronary vascularization. These mechanical effects are determinants of vessel diameters and composition of their walls. Arterial and venous specification is also affected by blood flow as indicated by endothelial phenotype changes that can occur in response to altered perfusion.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hanze J, Weissmann N, Grimminger F, Seeger W, Rose F (2007) Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling. Thromb Haemost 97:774–787
Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86:236–242
Semenza GL (2010) Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol 30:648–652
Iyer NV, Kotch LE, Agani F et al (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Gene Dev 12:149–162
Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684
Manalo DJ, Rowan A, Lavoie T et al (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105:659–669
Kelly BD, Hackett SF, Hirota K et al (2003) Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res 93:1074–1081
Bosch-Marce M, Okuyama H, Wesley JB et al (2007) Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res 101:1310–1318
Nomura M, Yamagishi S, Harada S et al (1995) Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 270:28316–28324
Yamagishi S, Yonekura H, Yamamoto Y, Fujimori H, Sakurai S, Tanaka N et al (1999) Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab Invest 79:501–509
Duan LJ, Zhang-Benoit Y, Fong GH (2005) Endothelium-intrinsic requirement for Hif-2alpha during vascular development. Circulation 111:2227–2232
Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC (2007) Acute postnatal ablation of HIF-2alpha results in anemia. Proc Natl Acad Sci U S A 104:2301–2306
Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667
Marti HH, Risau W (1998) Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci U S A 95:15809–15814
Li B, Sharpe EE, Maupin AB et al (2006) VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497
Torry RJ, Tomanek RJ, Zheng W et al (2009) Hypoxia increases placenta growth factor expression in human myocardium and cultured neonatal rat cardiomyocytes. J Heart Lung Transplant 28:183–190
Gerhardt H, Golding M, Fruttiger M et al (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177
Tang N, Wang L, Esko J et al (2004) Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6:485–495
Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S et al (2009) Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood 114:469–477
Van den Eijnde SM, Wenink AC, Vermeij-Keers C (1992) Origin of subepicardial cells in rat embryos. Anat Rec 242:96–102
Manasek FJ (1968) Embryonic development of the heart I. A light and electron microscopic study of myocardial development in the early chick embryo. J Morphol 125:329–365
Viragh S, Gittenberger-de Groot AC, Poelmann RE, Kalman F (1993) Early development of quail heart epicardium and associated vascular and glandular structures. Anat Embryol (Berl) 188:381–393
Nahirney PC, Mikawa T, Fischman DA (2003) Evidence for an extracellular matrix bridge guiding proepicardial cell migration to the myocardium of chick embryos. Dev Dyn 27:511–523
Mikawa T, Fischman DA (1992) Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels. Proc Natl Acad Sci U S A 89:9504–9508
Red-Horse K, Ueno H, Weissman IL, Krasnow MA (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464:549–553
Morabito CJ, Dettman RW, Kattan J, Collier JM, Bristow J (2001) Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Dev Biol 234:204–215
Yang K, Doughman YQ, Karunamuni G et al (2009) Expression of active notch1 in avian coronary development. Dev Dyn 238:162–170
Tomanek RJ, Ratajska A, Kitten GT, Yue X, Sandra A (1999) Vascular endothelial growth factor expression coincides with coronary vasculogenesis and angiogenesis. Dev Dyn 215:54–61
Druyan S, Cahaner A, Ashwell CM (2007) The expression patterns of hypoxia-inducing factor subunit alpha-1, heme oxygenase, hypoxia upregulated protein 1, and cardiac troponin T during development of the chicken heart. Poul Sci 86:2384–2389
Lee YM, Jeong CH, Koo SY et al (2001) Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev Dyn 220:175–186
Nanka O, Valasek P, Dvorakova M, Grim M (2006) Experimental hypoxia and embryonic angiogenesis. Dev Dyn 235:723–733
Nanka O, Krizova P, Fikrle M et al (2008) Abnormal myocardial and coronary vasculature development in experimental hypoxia. Anat Rec (Hoboken) 291:1187–1199
Wikenheiser J, Wolfram JA, Gargesha M, Yang K, Karunamuni G, Wilson DL et al (2009) Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn 238:2688–2700
Yue X, Tomanek RJ (1999) Stimulation of coronary vasculogenesis/angiogenesis by hypoxia in cultured embryonic hearts. Dev Dyn 216:28–36
Yue X, Tomanek RJ (2001) Effects of VEGF(165) and VEGF(121) on vasculogenesis and angiogenesis in cultured embryonic quail hearts. Am J Physiol Heart Circ Physiol 280:H2240–H2247
Tomanek RJ, Holifield JS, Reiter RS, Sandra A, Lin JJ (2002) Role of VEGF family members and receptors in coronary vessel formation. Dev Dyn 225:233–240
Enholm B, Paavonen K, Ristimaki A et al (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14:2475–2483
Ramirez-Bergeron DL, Runge A et al (2004) Hypoxia affects mesoderm and enhances hemangioblast specification during early development. Development 131:4623–4634
Han Y, Kuang SZ, Gomer A, Ramirez-Bergeron DL (2010) Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner. Stem Cells 28:799–809
Shalaby F, Rossant J, Yamaguchi TP et al (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66
Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70
Mascio CE, Olison AK, Ralphe JC et al (2005) Myocardial vascular and metabolic adaptations in chronically anemic fetal sheep. Am J Physiol Regul Integr Comp Physiol 289:R1736–R1745
Davis LE, Hohimer AR (1991) Hemodynamics and organ blood flow in fetal sheep subjected to chronic anemia. Am J Physiol 261:R1542–R1548
Davis LE, Hohimer AR, Morton MJ (1999) Myocardial blood flow and coronary reserve in chronically anemic fetal lambs. Am J Physiol 1999(277):R306–R313
Martin C, Yu AY, Jiang BH et al (1998) Cardiac hypertrophy in chronically anemic fetal sheep: Increased vascularization is associated with increased myocardial expression of vascular endothelial growth factor and hypoxia-inducible factor 1. Am J Obstet Gynecol 178:527–534
Reller MD, Morton MJ, Giraud GD, Wu DE, Thornburg KL (1992) Maximal myocardial blood flow is enhanced by chronic hypoxemia in late gestation fetal sheep. Am J Physiol 263(4pt 2):H1327–H1329
Wothe D, Hohimer A, Morton M et al (2002) Increased coronary blood flow signals growth of coronary resistance vessels in near-term ovine fetuses. Am J Physiol Regul Integr Comp Physiol 282:R295–R302
Torry RJ, O’Brien DM, Connell PM, Tomanek RJ (1992) Dipyridamole-induced capillary growth in normal and hypertrophic hearts. Am J Physiol 262:H980–H986
Pohl U (1990) Endothelial cells as part of a vascular oxygen-sensing system: hypoxia-induced release of autacoids. Experientia 46:1175–1179
Kourembanas S, Morita T, Liu Y, Christou H (1997) Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature. Kidney Int 51:438–443
Reller MD, Burson MA, Lohr JL, Morton MJ, Thornburg KL (1995) Nitric oxide is an important determinant of coronary flow at rest and during hypoxemic stress in fetal lambs. Am J Physiol 269:H2074–H2081
Xue C, Rengasamy A, Le Cras TD et al (1994) Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia. Am J Physiol 267:L667–L678
Dong Y, Thompson LP (2006) Differential expression of endothelial nitric oxide synthase in coronary and cardiac tissue in hypoxic fetal guinea pig hearts. J Soc Gynecol Invest 13:483–490
Thompson LP, Aguan K, Pinkas G, Weiner CP (2000) Chronic hypoxia increases the NO contribution of acetylcholine vasodilation of the fetal guinea pig heart. Am J Physiol Regul Integr Comp Physiol 279:R1813–R1820
Thornburg KL, Reller MD (1999) Coronary flow regulation in the fetal sheep. Am J Physiol 277:R1249–R1260
Ando K, Nakajima Y, Yamagishi T, Yamamoto S, Nakamura H (2004) Development of proximal coronary arteries in quail embryonic heart: multiple capillaries penetrating the aortic sinus fuse to form main coronary trunk. Circ Res 94:346–352
Velkey JM, Bernanke DH (2001) Apoptosis during coronary artery orifice development in the chick embryo. Anat Rec 262:310–317
Bogers AJ, Gittenberger-de Groot AC, Poelmann RE, Peault BM, Huysmans HA (1989) Development of the origin of the coronary arteries, a matter of ingrowth or outgrowth? Anat Embryol (Berl) 180:437–441
Poelmann RE, Gittenberger-de Groot AC, Mentink MM, Bokenkamp R, Hogers B (1993) Development of the cardiac coronary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras. Circ Res 73:559–568
Waldo KL, Kumiski DH, Kirby ML (1994) Association of the cardiac neural crest with development of the coronary arteries in the chick embryo. Anat Rec 239:315–331
Tomanek RJ, Haung L, Suvarna PR, O’Brien LC, Ratajska A, Sandra A (1996) Coronary vascularization during development in the rat and its relationship to basic fibroblast growth factor. Cardiovasc Res 31:E116–E126
Tomanek RJ, Ishii Y, Holifield JS et al (2006) VEGF family members regulate myocardial tubulogenesis and coronary artery formation in the embryo. Circ Res 98:947–953
Hood LC, Rosenquist TH (1992) Coronary artery development in the chick: origin and deployment of smooth muscle cells, and the effects of neural crest ablation. Anat Rec 234:291–300
Mikawa T, Gourdie RG (1996) Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev Biol 174:221–232
Dettman RW, Denetclaw W Jr, Ordahl CP, Bristow J (1998) Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Dev Biol 193:169–181
Gittenberger-de Groot A, Vrancken Peeters MP, Mentink M, Gourdie R, Poelmann R (1998) Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ Res 82:1043–1052
Perez-Pomares JM, Carmona R, Gonzalez-Iriarte M et al (2002) Origin of coronary endothelial cells from epicardial mesothelium in avian embryos. Int J Dev Biol 46:1005–1013
Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127:1607–1616
Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055
Sridurongrit S, Larsson J, Schwartz R, Ruiz-Lozano P, Kaartinen V (2008) Signaling via the Tgf-beta type I receptor Alk5 in heart development. Dev Biol 322:208–218
Tomanek RJ, Hansen HK, Christensen LP (2008) Temporally expressed PDGF and FGF-2 regulate embryonic coronary artery formation and growth. Arterioscler Thromb Vasc Biol 28:1237–1243
Azambuja AP, Portillo-Sanchez V, Rodrigues MV et al (2010) Retinoic acid and VEGF delay smooth muscle relative to endothelial differentiation to coordinate inner and outer coronary vessel wall morphogenesis. Cir Res 107:204–216
Pistea A, Bakker EN, Spaan JA, VanBavel E (2005) Flow inhibits inward remodeling in cannulated porcine small coronary arteries. Am J Physiol Heart Circ Physiol 289:H2632–H2640
Tornling G (1982) Capillary neoformation in the heart of dipyridamole-treated rats. Acta Pathol Microbiol Immunol Scand A 90:269–271
Mall G, Schikora I, Mattfeldt T, Bodle R (1987) Dipyridamole-induced neoformation of capillaries in the rat heart. Quantitative stereological study on papillary muscles. Lab Invest 57:86–93
Chien S, Li S, Shyy YJ (1998) Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension 31:162–169
Li YS, Haga JH, Chien S (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 38:1949–1971
Yamamoto K, Ando J (2011) New molecular mechanisms for cardiovascular disease: blood flow sensing mechanism in vascular endothelial cells. J Pharmacol Sci 116:323–331
Bao X, Lu C, Frangos JA (2001) Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells. Am J Physiol Heart Circ Physiol 281:H22–H29
Chiu JJ, Wung BS, Shyy JY, Hsieh HJ, Wang DL (1997) Reactive oxygen species are involved in shear stress-induced intercellular adhesion molecule-1 expression in endothelial cells. Arterioscler Thromb Vasc Biol 17:3570–3577
Wang DZ, Li S, Hockemeyer D et al (2002) Potentiation of serum response factor activity by a family of myocardin-related transcription factors. Proc Natl Acad Sci U S A. 99:14855–14860
Chiquet M (1999) Regulation of extracellular matrix gene expression by mechanical stress. Matrix Biol 18:417–426
Fan J, Walsh KB (1999) Mechanical stimulation regulates voltage-gated potassium currents in cardiac microvascular endothelial cells. Circ Res 84:451–457
Fisslthaler B, Popp R, Michaelis UR et al (2001) Cyclic stretch enhances the expression and activity of coronary endothelium-derived hyperpolarizing factor synthase. Hypertension 38:1427–1432
Sokabe M, Naruse K, Sai S, Yamada T, Kawakami K, Inoue M et al (1999) Mechanotransduction and intracellular signaling mechanisms of stretch-induced remodeling in endothelial cells. Heart Vessels Suppl 12:191–193
Zheng W, Seftor EA, Meininger CJ, Hendrix MJ, Tomanek RJ (2001) Mechanisms of coronary angiogenesis in response to stretch: role of VEGF and TGF-beta. Am J Physiol Heart Circ Physiol 280:H909–H917
Zheng W, Christensen LP, Tomanek RJ (2004) Stretch induces upregulation of key tyrosine kinase receptors in microvascular endothelial cells. Am J Physiol Heart Circ Physiol. 2004(287):H2739–H2745
Chang H, Wang BW, Kuan P, Shyu KG (2003) Cyclical mechanical stretch enhances angiopoietin-2 and Tie2 receptor expression in cultured human umbilical vein endothelial cells. Clin Sci (Lond) 104:421–428
Li J, Hampton T, Morgan JP, Simons M (1997) Stretch-induced VEGF expression in the heart. J Clin Invest 100:18–24
Batra S, Rakusan K (1992) Capillary network geometry during postnatal growth in rat hearts. Am J Physiol 262:H635–H640
Tomanek RJ, Doty MK, Sandra A (1998) Early coronary angiogenesis in response to thyroxine: growth characteristics and upregulation of basic fibroblast growth factor. Circ Res 82:587–593
Dbaly J (1773) Postnatal development of coronary arteries in the rat. J Anat Entwickl-Gesch 141:89–101
Ito T, Harada K, Tamura M, Takada G (1998) In situ morphometric analysis of the coronary arterial growth in perinatal rats. Early Hum Dev 52:21–26
Yasuoka K, Harada K, Tamura M, Takada G (2002) Left anterior descending coronary artery flow and its relation to age in children. J Am Soc Echocardiogr 15:69–75
Kurosawa S, Kurosawa H, Becker AE (1986) The coronary arterioles in newborns, infants and children. A morphometric study of normal hearts and hearts with aortic atresia and complete transposition. Int J Cardiol 10:43–56
Wiest G, Gharehbaghi H, Amann K et al (1992) Physiological growth of arteries in the rat heart parallels the growth of capillaries, but not of myocytes. J Mol Cell Cardiol 24:1423–1431
Ohuchi H, Beighley PE, Dong Y, Zamir M, Ritman EL (2007) Microvascular development in porcine right and left ventricular walls. Pediatr Res 61:676–680
Zamir M (2005) The physics of coronary blood flow. Springer, New York
Fisher DJ, Heymann MA, Rudolph AM (1982) Regional myocardial blood flow and oxygen delivery in fetal, newborn, and adult sheep. Am J Physiol 243:H729–H731
dela Paz NG, D’Amore PA (2009) Arterial versus venous endothelial cells. Cell Tissue Res 335:5–16
Eichmann A, Yuan L, Moyon D et al (2005) Vascular development: from precursor cells to branched arterial and venous networks. Int J Dev Biol 49:259–267
le Noble F, Moyon D, Pardanaud L et al (2004) Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development 131:361–375
Jones EA, le Noble F, Eichmann A (2006) What determines blood vessel structure? Genetic prespecification vs. hemodynamics. Physiology (Bethesda) 21:388–395
Moyon D, Pardanaud L, Yuan L, Breant C, Eichmann A (2001) Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development 128:3359–3370
Haga JH, Li YS, Chien S (2007) Molecular basis of the effects of mechanical stretch on vascular smooth muscle cells. J Biomech 40:947–960
Acknowledgments
This work was supported by funds from the National Institutes of Health grant 5 R01 075446.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Tomanek, R.J. (2013). Hypoxia and Mechanical Factors Drive Coronary Vascular Development . In: Ostadal, B., Dhalla, N. (eds) Cardiac Adaptations. Advances in Biochemistry in Health and Disease, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5203-4_4
Download citation
DOI: https://doi.org/10.1007/978-1-4614-5203-4_4
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-5202-7
Online ISBN: 978-1-4614-5203-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)