This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, Y. F. Articles by Epstein, S. E. Search for Related Content PubMed PubMed Citation Articles by Zhou, Y. F. Articles by Epstein, S. E.

Effects of gene delivery on collateral development in chronic hypoperfusion

Diverse effects of angiopoietin-1 versus vascular endothelial growth factor

Vascular Biology Laboratory, Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA

Manuscript received January 30, 2004; revised manuscript received April 27, 2004, accepted May 2, 2004.

^* Reprint requests and correspondence: Dr. Yi Fu Zhou, Vascular Biology Laboratory, Cardiovascular Research Institute, GHRB-217, 108 Irving Street, Washington Hospital Center, Washington, DC 20010 (Email: yzhou21{at}jhmi.edu).

OBJECTIVES: The aim of this research was to test the effects of vascular endothelial growth factor (VEGF)/angiopoietin-1 (Ang-1) on adult hypoperfused tissues.

BACKGROUND: Angiopoietin-1 and VEGF act separately and synergistically in vascular development during embryogenesis. However, little is known regarding their relative roles in collateral development after chronic arterial obstruction and tissue ischemia in the adult.

METHODS: Central and caudal ear arteries of 32 rabbits were ligated to induce ischemia. At two months, when flow was about 65% of pre-ligation values, we injected intradermally 10⁹ plaque-forming unit adenovirus with the following transgenes: Ang-1, VEGF, or a combination of both. Ear perfusion was followed up for four weeks, and vessel leakage was assessed by Evens Blue test.

RESULTS: Before injection, flow was 65% of baseline, and endogenous VEGF levels in ischemic tissue were increased. Adenovirus-encoding VEGF gene (Ad.VEGF) at one week caused a visible inflammatory response associated with a 24% flow increase (p = 0.018). Adenovirus-encoding Ang-1 gene (Ad.Ang-1) increased flow 22% (p = 0.004) with no visible inflammation; Ad.VEGF caused three times as much vessel leakage as Ad.Ang-1 (142.5 ± 38 vs. 49.5 ± 9.8 ng Evens Blue/mg tissue; p < 0.001). However, at four weeks, compared with baseline, VEGF decreased flow 18% (p = 0.004), whereas Ang-1 increased tissue perfusion 26% (p < 0.001). This effect was abolished when Ad.Ang-1 was injected with soluble VEGF receptor [Ad.Flt(1-3)-Fc], which blocks VEGF-dependent signaling. Exogenous Ang-1 did not increase perfusion in a normally perfused ear, in which endogenous VEGF is not expressed.

CONCLUSIONS: Exogenous Ang-1 enhances perfusion in hypoperfused tissues only in the presence of increased levels of endogenous VEGF. Overexpression of VEGF, however, after causing an inflammatory response, does not improve collateral blood flow.

Abbreviations and Acronyms   Ad.Ang-1 = adenovirus-encoding Ang-1 gene   Ad.Flt(1-3)-Fc = adenovirus-encoding soluble VEGF receptor gene   Ad.Null = control adenovirus without transgene insert   Ad.VEGF = adenovirus-encoding VEGF gene   Ang-1 = angiopoietin-1   Flt(1-3)-Fc = soluble VEGF receptor gene   PFU = plaque-forming unit   VEGF = vascular endothelial growth factor

This article has been cited by other articles:

				K. A. Horvath and Y. Zhou Transmyocardial Laser Revascularization and Extravascular Angiogenetic Techniques to Increase Myocardial Blood Flow Card. Surg. Adult, January 1, 2008; 3(2008): 733 - 752. [Full Text]

				Y. Reiss, J. Droste, M. Heil, S. Tribulova, M. H.H. Schmidt, W. Schaper, D. J. Dumont, and K. H. Plate Angiopoietin-2 Impairs Revascularization After Limb Ischemia Circ. Res., July 6, 2007; 101(1): 88 - 96. [Abstract] [Full Text] [PDF]

				L. Ye, H. K. Haider, S. Jiang, R. S. Tan, W. C. Toh, R. Ge, and E. K.W. Sim Angiopoietin-1 for myocardial angiogenesis: A comparison between delivery strategies Eur J Heart Fail, May 1, 2007; 9(5): 458 - 465. [Abstract] [Full Text] [PDF]

				G. von Degenfeld, A. Banfi, M. L. Springer, R. A. Wagner, J. Jacobi, C. R. Ozawa, M. J. Merchant, J. P. Cooke, and H. M. Blau Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia FASEB J, December 1, 2006; 20(14): 2657 - 2659. [Abstract] [Full Text] [PDF]

				A. C. Aplin, M. Gelati, E. Fogel, E. Carnevale, and R. F. Nicosia Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis Physiol Genomics, October 3, 2006; 27(1): 20 - 28. [Abstract] [Full Text] [PDF]

				S. Jiang, H. Kh. Haider, N. M. Idris, A. Salim, and M. Ashraf Supportive Interaction Between Cell Survival Signaling and Angiocompetent Factors Enhances Donor Cell Survival and Promotes Angiomyogenesis for Cardiac Repair Circ. Res., September 29, 2006; 99(7): 776 - 784. [Abstract] [Full Text] [PDF]

				F. Baffert, T. Le, G. Thurston, and D. M. McDonald Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H107 - H118. [Abstract] [Full Text] [PDF]

				C.-H. Cho, K. E. Kim, J. Byun, H.-S. Jang, D.-K. Kim, P. Baluk, F. Baffert, G. M. Lee, N. Mochizuki, J. Kim, et al. Long-Term and Sustained COMP-Ang1 Induces Long-Lasting Vascular Enlargement and Enhanced Blood Flow Circ. Res., July 8, 2005; 97(1): 86 - 94. [Abstract] [Full Text] [PDF]