Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines.

BACKGROUND The impact of hyperlipidemia on collateral vessel development in vivo remains enigmatic. We sought to determine the anatomic extent and functional capacity of the collateral bed that develops in response to limb ischemia in a well characterized animal model of spontaneous hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit. We further characterized the impact of exogenous angiogenic cytokine administration on collateral vessel development and function in the same animal model. METHODS AND RESULTS Weight-matched 6-month-old male homozygous WHHL (n=9) and normal New Zealand White (NZW) (n=9) rabbits underwent surgical resection of one femoral artery. Ten days later, the ischemic hindlimb was evaluated for collateral vessel formation, blood flow, and tissue damage. Collateral vasculature was less extensive among WHHL than NZW, as indicated by a significant reduction in angiographic score (0.19+/-0.02 versus 0.35+/-0.03, P<.001) and capillary density (46.4+/-4.1 versus 78.9+/-4.6/mm2, P<.0002). This was associated with a reduction in calf blood pressure index (9.5+/-3.5% versus 32.8+/-2.8%, P<.0001), arterial blood flow (7.5+/-0.6 versus 13.6+/-0.7 mL/min, P<.0001), and muscle perfusion index (40.1+/-3.2% versus 65.9+/-2.0%, P<.0001) and an increase in muscle necrosis (48.16+/-5.41% versus 25.90+/-3.83% negative 2,3,5-triphenyltetrazolium chloride staining, P<.004). Treatment of WHHL rabbits (n=9) with recombinant human vascular endothelial growth factor produced a statistically significant improvement in all functional as well as anatomic indices of collateral development. CONCLUSIONS Collateral vessel development associated with hindlimb ischemia in vivo is severely attenuated in an animal model of spontaneous hypercholesterolemia but nevertheless may be augmented by administration of angiogenic cytokines.

[1]  J. Isner,et al.  Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer. , 1996, Circulation.

[2]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[3]  P. Fox,et al.  Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein. , 1996, The Journal of clinical investigation.

[4]  B. Keyt,et al.  The in vivo bioactivity of vascular endothelial growth factor/vascular permeability factor is independent of N-linked glycosylation. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[5]  B. Keyt,et al.  Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. , 1996, The Journal of clinical investigation.

[6]  Atsushi Namiki,et al.  Hypoxia Induces Vascular Endothelial Growth Factor in Cultured Human Endothelial Cells (*) , 1995, The Journal of Biological Chemistry.

[7]  J. Isner,et al.  Time course of increased cellular proliferation in collateral arteries after administration of vascular endothelial growth factor in a rabbit model of lower limb vascular insufficiency. , 1995, The American journal of pathology.

[8]  W. Risau.  Differentiation of endothelium , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  J. Isner,et al.  Recovery of disturbed endothelium-dependent flow in the collateral-perfused rabbit ischemic hindlimb after administration of vascular endothelial growth factor. , 1995, Circulation.

[10]  J. Isner,et al.  Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. , 1995, Circulation.

[11]  Jason A. Lowry,et al.  Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. , 1995, Circulation.

[12]  E. Brogi,et al.  Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. , 1994, The Journal of clinical investigation.

[13]  C M Bloor,et al.  Coronary collateral development in swine after coronary artery occlusion. , 1992, Circulation research.

[14]  H. M. Payne,et al.  Validation of A Doppler Guide Wire for Intravascular Measurement of Coronary Artery Flow Velocity , 1992, Circulation.

[15]  R. Virmani,et al.  Watanabe heritable hyperlipidemic rabbits. Familial hypercholesterolemia. , 1992, The American journal of pathology.

[16]  L. Pitts,et al.  Evaluation of 2,3,5‐Triphenyltetrazolium Chloride Staining To Delineate Rat Brain Infarcts , 1991, Stroke.

[17]  S. Epstein,et al.  Heparin promotes the formation of extracardiac to coronary anastomoses in a canine model. , 1991, The American journal of physiology.

[18]  G. Heusch,et al.  Measurement of Regional Myocardial Blood Flow With Multiple Colored Microspheres* , 1991, Circulation.

[19]  M. Nakamura,et al.  Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits. , 1991, Circulation research.

[20]  D. Harrison,et al.  Endothelial modulation of the coronary vasculature in vessels perfused via mature collaterals. , 1990, Circulation.

[21]  R. Virmani,et al.  Vascular reactivity during the progression of atherosclerotic plaque. A study in Watanabe heritable hyperlipidemic rabbits. , 1990, Circulation research.

[22]  K. Kugiyama,et al.  Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins , 1990, Nature.

[23]  A. Ziada,et al.  The effect of long-term vasodilatation on capillary growth and performance in rabbit heart and skeletal muscle. , 1984, Cardiovascular research.

[24]  T. Kita,et al.  Cellular Pathology of Progressive Atherosclerosis in the WHHL Rabbit: An Animal Model of Familial Hypercholesterolemia , 1983, Arteriosclerosis.

[25]  Y. Tsujita,et al.  WHHL‐Rabbit: a low density lipoprotein receptor‐deficient animal model for familial hypercholesterolemia , 1980, FEBS letters.

[26]  Y. Watanabe.  Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). , 1980, Atherosclerosis.

[27]  C. Bauters,et al.  Basic fibroblast growth factor restores endothelium-dependent responses after balloon injury of rabbit arteries. , 1996, Circulation.

[28]  Hai Hoang Nguyen,et al.  Rapid communication Basic fibroblast growth factor reverses atherosclerotic impairment of human coronary angiogenesis-like responses in vitro* , 1995 .

[29]  R. Thompson,et al.  Mechanisms of angiogenesis. , 1987, Annual review of physiology.