(Circulation. 1995;91:2802-2809.)
© 1995 American Heart Association, Inc.
Articles |
Recovery of Disturbed Endothelium-Dependent Flow in the Collateral-Perfused Rabbit Ischemic Hindlimb After Administration of Vascular Endothelial Growth Factor
From the Departments of Medicine (Cardiology) (J.M.I.), Surgery (Cardiovascular) (J.F.S.), and Biomedical Research (C.B., T.A., L.P.Z., S.T., J.M.I.), St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass; and the Department of Cardiovascular Research (S.B., N.F.), Genentech Inc, South San Francisco, Calif.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135.
Background Disturbed endothelium-dependent blood flow has been shown to be a feature of native collateral vessels. Recent studies have shown that recombinant angiogenic growth factors augment collateral development in animal models of hindlimb ischemia. We therefore investigated the hypothesis that the administration of an angiogenic growth factor, in this case vascular endothelial growth factor (VEGF), may promote recovery of disturbed endothelium-dependent blood flow in a rabbit model of hindlimb ischemia.
Methods and Results Ischemia was induced by ligation of the external iliac artery and excision of the femoral artery in one limb of New Zealand White rabbits (day 0). Flow velocity was measured using a Doppler guide wire at rest and after administration of serotonin and acetylcholine. Blood flow (in mL/min) was calculated assuming a circular lumen geometry. In untreated control animals with an ischemic limb, serotonin administered at day 10 or 40 produced a decrease in hindlimb blood flow (71±2% and 33±6% reduction from baseline, respectively); in contrast, among animals treated with a single 500-µg bolus dose of VEGF administered selectively into the internal iliac artery at day 10 and studied at day 40, serotonin produced an increase in flow (119±8% from baseline; P<.05 versus control animals). Acetylcholine induced only a moderate increase in flow in control animals (152±15% at day 10 and 177±14% at day 40) in contrast to a profound increase among VEGF-treated animals studied at day 40 (254±25%; P<.05 versus control animals).
Conclusions To our knowledge, these findings constitute the first demonstration of successful pharmacological modulation of disturbed endothelium-dependent flow in the arterial circulation subserved by collateral vessels. This physiological benefit complements previously reported anatomic findings suggesting a favorable impact of angiogenic growth factors on collateral-dependent limb ischemia.
Key Words: growth factors • ischemia • vasomotion • serotonin • acetylcholine
This article has been cited by other articles:
 |
|
 |
|
  C Kalka and I. Baumgartner Gene and stem cell therapy in peripheral arterial occlusive disease Vascular Medicine, May 1, 2008; 13(2): 157 - 172. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Ishikawa, M. Eguchi, M. Wada, Y. Iwami, K. Tono, H. Iwaguro, H. Masuda, T. Tamaki, and T. Asahara Establishment of a Functionally Active Collagen-Binding Vascular Endothelial Growth Factor Fusion Protein In Situ Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 1998 - 2004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kobayashi, T. Kondo, N. Inoue, M. Aoki, M. Mizuno, K. Komori, J. Yoshida, and T. Murohara Combination of In Vivo Angiopoietin-1 Gene Transfer and Autologous Bone Marrow Cell Implantation for Functional Therapeutic Angiogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1465 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Grover, T. A. Parker, N. E. Markham, and S. H. Abman rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L315 - L321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Irie, T. Tatsumi, M. Takamiya, K. Zen, T. Takahashi, A. Azuma, K. Tateishi, T. Nomura, H. Hayashi, N. Nakajima, et al. Carbon Dioxide-Rich Water Bathing Enhances Collateral Blood Flow in Ischemic Hindlimb via Mobilization of Endothelial Progenitor Cells and Activation of NO-cGMP System Circulation, March 29, 2005; 111(12): 1523 - 1529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Suda, L. A. Smith, L. V. d'Uscio, T. E. Peterson, and Z. S. Katusic In Vivo Expression of Recombinant Vascular Endothelial Growth Factor in Rabbit Carotid Artery Increases Production of Superoxide Anion Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 506 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Segev, N. Nili, and B. H Strauss The role of perlecan in arterial injury and angiogenesis Cardiovasc Res, September 1, 2004; 63(4): 603 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higashi, M. Kimura, K. Hara, K. Noma, D. Jitsuiki, K. Nakagawa, T. Oshima, K. Chayama, T. Sueda, C. Goto, et al. Autologous Bone-Marrow Mononuclear Cell Implantation Improves Endothelium-Dependent Vasodilation in Patients With Limb Ischemia Circulation, March 16, 2004; 109(10): 1215 - 1218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Buckwalter, V. C. Curtis, Z. Valic, S. B. Ruble, and P. S. Clifford Endogenous vascular remodeling in ischemic skeletal muscle: a role for nitric oxide J Appl Physiol, March 1, 2003; 94(3): 935 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Grover, T. A. Parker, J. P. Zenge, N. E. Markham, J. P. Kinsella, and S. H. Abman Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus Am J Physiol Lung Cell Mol Physiol, March 1, 2003; 284(3): L508 - L517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Amano, H. Matsubara, O. Iba, M. Okigaki, S. Fujiyama, T. Imada, H. Kojima, Y. Nozawa, S. Kawashima, M. Yokoyama, et al. Enhancement of Ischemia-Induced Angiogenesis by eNOS Overexpression Hypertension, January 1, 2003; 41(1): 156 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kobayashi and K. Kamata Short-term insulin treatment and aortic expressions of IGF-1 receptor and VEGF mRNA in diabetic rats Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1761 - H1768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Janiak, P. Lainee, Y. Grataloup, C.-E. Luyt, J.-P. Bidouard, J.-B. Michel, S. E O'Connor, and J.-M. Herbert Serotonin receptor blockade improves distal perfusion after lower limb ischemia in the fatty Zucker rat Cardiovasc Res, November 1, 2002; 56(2): 293 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. B. Lemstrom, R. Krebs, A. I. Nykanen, J. M. Tikkanen, R. K. Sihvola, E. M. Aaltola, P. J. Hayry, J. Wood, K. Alitalo, S. Yla-Herttuala, et al. Vascular Endothelial Growth Factor Enhances Cardiac Allograft Arteriosclerosis Circulation, May 28, 2002; 105(21): 2524 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-H. Liu, H. Jin, H. S. Floten, Z. Ren, A. P.C. Yim, and G.-W. He Vascular endothelial growth factor-mediated, endothelium-dependent relaxation in human internal mammary artery Ann. Thorac. Surg., March 1, 2002; 73(3): 819 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rajagopalan, M. Shah, A. Luciano, R. Crystal, and E. G. Nabel Adenovirus-Mediated Gene Transfer of VEGF121 Improves Lower-Extremity Endothelial Function and Flow Reserve Circulation, August 14, 2001; 104(7): 753 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lu, J. Shansky, M. Del Tatto, P. Ferland, X. Wang, and H. Vandenburgh Recombinant Vascular Endothelial Growth Factor Secreted From Tissue-Engineered Bioartificial Muscles Promotes Localized Angiogenesis Circulation, July 31, 2001; 104(5): 594 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Partovian, S. Adnot, B. Raffestin, V. Louzier, M. Levame, I. M. Mavier, P. Lemarchand, and S. Eddahibi Adenovirus-Mediated Lung Vascular Endothelial Growth Factor Overexpression Protects against Hypoxic Pulmonary Hypertension in Rats Am. J. Respir. Cell Mol. Biol., December 1, 2000; 23(6): 762 - 771. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Yasuda, Y. Goto, T. Baba, T. Satoh, H. Sumida, S. Miyazaki, and H. Nonogi Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function J. Am. Coll. Cardiol., July 1, 2000; 36(1): 115 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Zachary, A. Mathur, S. Yla-Herttuala, and J. Martin Vascular Protection : A Novel Nonangiogenic Cardiovascular Role for Vascular Endothelial Growth Factor Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1512 - 1520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Schwarz, M. T. Speakman, M. Patterson, S. S. Hale, J. M. Isner, L. H. Kedes, and R. A. Kloner Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat--angiogenesis and angioma formation J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1323 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Poliakova, I. Kovesdi, X. Wang, M. C. Capogrossi, and M. Talan VASCULAR PERMEABILITY EFFECT OF ADENOVIRUS-MEDIATED VASCULAR ENDOTHELIAL GROWTH FACTOR GENE TRANSFER TO THE RABBIT AND RAT SKELETAL MUSCLE J. Thorac. Cardiovasc. Surg., August 1, 1999; 118(2): 339 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. SCALIA, G. BOOTH, and D. J. LEFER Vascular endothelial growth factor attenuates leukocyte–endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide FASEB J, June 1, 1999; 13(9): 1039 - 1046. [Abstract] [Full Text]
|
|
|
|
|
|
I. J. Kullo, R. D. Simari, and R. S. Schwartz Vascular Gene Transfer : From Bench to Bedside Arterioscler. Thromb. Vasc. Biol., February 1, 1999; 19(2): 196 - 207. [Full Text] [PDF]
|
|
|
|
|
|
S. Takeshita, T. Isshiki, M. Ochiai, K. Eto, H. Mori, E. Tanaka, K. Umetani, and T. Sato Endothelium-Dependent Relaxation of Collateral Microvessels After Intramuscular Gene Transfer of Vascular Endothelial Growth Factor in a Rat Model of Hindlimb Ischemia Circulation, September 29, 1998; 98(13): 1261 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. T. Yang, R. W. Ogilvie, and R. L. Terjung Exercise training enhances basic fibroblast growth factor-induced collateral blood flow Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H2053 - H2061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Horowitz, A. Rivard, R. van der Zee, M. Hariawala, D. D. Sheriff, D. D. Esakof, G. M. Chaudhry, J. F. Symes, and J. M. Isner Vascular Endothelial Growth Factor/Vascular Permeability Factor Produces Nitric Oxide–Dependent Hypotension : Evidence for a Maintenance Role in Quiescent Adult Endothelium Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 2793 - 2800. [Abstract] [Full Text]
|
|
|
|
|
|
E. Van Belle, A. Rivard, D. Chen, M. Silver, S. Bunting, N. Ferrara, J. F. Symes, C. Bauters, and J. M. Isner Hypercholesterolemia Attenuates Angiogenesis but Does Not Preclude Augmentation by Angiogenic Cytokines Circulation, October 21, 1997; 96(8): 2667 - 2674. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. L. Wong, Z. A. Haroon, S. Werner, M. W. Dewhirst, C. S. Greenberg, and K. G. Peters Tie2 Expression and Phosphorylation in Angiogenic and Quiescent Adult Tissues Circ. Res., October 19, 1997; 81(4): 567 - 574. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Luo, M. Diaco, T. Murohara, N. Ferrara, J. M. Isner, and J. F. Symes Vascular Endothelial Growth Factor Attenuates Myocardial Ischemia-Reperfusion Injury Ann. Thorac. Surg., October 1, 1997; 64(4): 993 - 998. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Hayashi, K. Abe, H. Suzuki, and Y. Itoyama Rapid Induction of Vascular Endothelial Growth Factor Gene Expression After Transient Middle Cerebral Artery Occlusion in Rats Stroke, October 1, 1997; 28(10): 2039 - 2044. [Abstract] [Full Text]
|
|
|
|
|
|
H. Tabata, M. Silver, and J. M Isner Arterial gene transfer of acidic fibroblast growth factor for therapeutic angiogenesis in vivo: critical role of secretion signal in use of naked DNA Cardiovasc Res, September 1, 1997; 35(3): 470 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S Lewis, M. Y Flugelman, A. Weisz, I. Keren-Tal, and W. Schaper Angiogenesis by gene therapy: a new horizon for myocardial revascularization? Cardiovasc Res, September 1, 1997; 35(3): 490 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ruef, Z. Y. Hu, L.-Y. Yin, Y. Wu, S. R. Hanson, A. B. Kelly, L. A. Harker, G. N. Rao, M. S. Runge, and C. Patterson Induction of Vascular Endothelial Growth Factor in Balloon-Injured Baboon Arteries : A Novel Role for Reactive Oxygen Species in Atherosclerosis Circ. Res., July 19, 1997; 81(1): 24 - 33. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. Abedi and I. Zachary Vascular Endothelial Growth Factor Stimulates Tyrosine Phosphorylation and Recruitment to New Focal Adhesions of Focal Adhesion Kinase and Paxillin in Endothelial Cells J. Biol. Chem., June 13, 1997; 272(24): 15442 - 15451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Pepper Manipulating Angiogenesis: From Basic Science to the Bedside Arterioscler. Thromb. Vasc. Biol., April 1, 1997; 17(4): 605 - 619. [Abstract] [Full Text]
|
|
|
|
|
|
R. van der Zee, T. Murohara, Z. Luo, F. Zollmann, J. Passeri, C. Lekutat, and J. M. Isner Vascular Endothelial Growth Factor/Vascular Permeability Factor Augments Nitric Oxide Release From Quiescent Rabbit and Human Vascular Endothelium Circulation, February 18, 1997; 95(4): 1030 - 1037. [Abstract] [Full Text]
|
|
|
|
|
|
N. Ferrara and T. Davis-Smyth The Biology of Vascular Endothelial Growth Factor Endocr. Rev., February 1, 1997; 18(1): 4 - 25. [Abstract] [Full Text]
|
|
|
|
|
|
E. Allaire and A. W. Clowes Endothelial Cell Injury in Cardiovascular Surgery: The Intimal Hyperplastic Response Ann. Thorac. Surg., February 1, 1997; 63(2): 582 - 591. [Abstract] [Full Text]
|
|
|
|
|
|
E. Van Belle, F. O. Tio, T. Couffinhal, L. Maillard, J. Passeri, and J. M. Isner Stent Endothelialization: Time Course, Impact of Local Catheter Delivery, Feasibility of Recombinant Protein Administration, and Response to Cytokine Expedition Circulation, January 21, 1997; 95(2): 438 - 448. [Abstract] [Full Text]
|
|
|
|
|
|
M. W. Majesky A Little VEGF Goes a Long Way: Therapeutic Angiogenesis by Direct Injection of Vascular Endothelial Growth Factor–Encoding Plasmid DNA Circulation, December 15, 1996; 94(12): 3062 - 3064. [Full Text]
|
|
|
|
|
|
Y. Tsurumi, S. Takeshita, D. Chen, M. Kearney, S. T. Rossow, J. Passeri, J. R. Horowitz, J. F. Symes, and J. M. Isner Direct Intramuscular Gene Transfer of Naked DNA Encoding Vascular Endothelial Growth Factor Augments Collateral Development and Tissue Perfusion Circulation, December 15, 1996; 94(12): 3281 - 3290. [Abstract] [Full Text]
|
|
|
|
|
|
T. Asahara, D. Chen, Y. Tsurumi, M. Kearney, S. Rossow, J. Passeri, J. F. Symes, and J. M. Isner Accelerated Restitution of Endothelial Integrity and Endothelium-Dependent Function After phVEGF165 Gene Transfer Circulation, December 15, 1996; 94(12): 3291 - 3302. [Abstract] [Full Text]
|
|
|
|
|
|
T. Meurice, C. Bauters, J.-L. Auffray, B. Vallet, M. Hamon, F. Valero, E. Van Belle, J.-M. Lablanche, and M. E. Bertrand Basic Fibroblast Growth Factor Restores Endothelium-Dependent Responses After Balloon Injury of Rabbit Arteries Circulation, January 1, 1996; 93(1): 18 - 22. [Abstract] [Full Text]
|
|
|
|
|
|
W. Casscells Growth Factor Therapies for Vascular Injury and Ischemia Circulation, June 1, 1995; 91(11): 2699 - 2702. [Full Text]
|
|