Angiogenic Responses of Vascular Endothelial Growth Factors in Periadventitial Tissue

Abstract

Recent discovery of new members of the vascular endothelial growth factor (VEGF) family has generated much interest as to which members may be best suited for therapeutic angiogenesis in various tissues. In this study we evaluated angiogenic responses of the different members of the VEGF family in vivo using adenoviral gene transfer. Adenoviruses (1 x 10(9) plaque-forming units [pfu]) encoding for VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-C(deltaNdeltaC) and VEGF-D(deltaNdeltaC) (deltaNdeltaC are proteolytically cleaved forms) were transferred locally to the periadventitial space of the rabbit carotid arteries using a collar technique that allows efficient local transfection of the periadventitial tissue. Expression of the transfected VEGFs was confirmed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Seven days after the gene transfer maximum neovessel formation was observed in VEGF-A-, VEGF-D-, and VEGF-D(deltaNdeltaC)-transfected arteries. VEGF-C(deltaNdeltaC) also showed angiogenic activity whereas VEGF-B was not effective in inducing angiogenesis. Pericytes were detected around the neovessels, which also frequently showed the presence of intraluminal erythrocytes. Infiltration of inflammatory cells in response to VEGF-D and VEGF-D(deltaNdeltaC) was less prominent than that caused by other VEGFs. In line with the absence of lymphatics in the normal carotid arteries no significant evidence of lymphatic vessel formation was seen in response to any of the studied VEGFs in the periadventitial space. The results help to define possibilities for local angiogenic therapy around blood vessels and support the concept that angiogenic effects may be tissue-specific and depend both on the growth factor ligands and the target tissues. It is concluded that VEGF-A, VEGF-D, and VEGF-D(deltaNdeltaC) are the best candidates for therapeutic angiogenesis when delivered around large arteries.

Vegf-B

“…This explains why most of the time VEGF-B did not induce blood vessels growth after protein or gene delivery. 5,7,9,33,34 On the other hand, under other conditions where blood vessels are challenged and need to struggle to survive, VEGF-B is then critically required and VEGF-B treatment can indeed lead to more (survived) blood vessels. 9,29,30,32 Under such conditions, VEGF-B can appear to be "angiogenic."…”

“…VEGF-B was reported to be angiogenic in some studies, [29][30][31][32] but lack of an angiogenic activity in others. 5,7,33,34 Below is an overview of the reports with regard to the angiogenic activity of VEGF-B.…”

“…33 Similarly, adenoviral gene transfer of VEGF-A and VEGF-D to adventitia induced robust adventitial angiogenesis, whereas VEGF-B adenoviral gene transfer failed to do so. 34,45 Another study also showed that VEGF-B 167 gene delivery to the skin or ischemic limb did not induce blood vessel growth. 10 Furthermore, VEGF-B 167 recombinant protein injection into mouse eyes at a dose effective for retinal neuron survival did not induce ocular angiogenesis.…”

Periadventitial angiopoietin-1 gene transfer induces angiogenesis in rabbit carotid arteries

“…[15][16][17] It has been used to improve vein graft survival. An ongoing clinical trial is using biodegradable collagen collars as a reservoir to deliver AdvVEGF-D for the prevention of vascular access stenosis.…”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…Furthermore, just noticing the angiogenic role of VEGF-B in vivo , an apparent disagreement exists ranging from no angiogenic ability at all in several tissues after adenovirus gene delivery; 87 ability to potentiate rather than bringing about angiogenesis when transduced into the endothelial barrier; 88 a restricted revascularization in the ischemic myocardium. 18 , 77 Several factors had been proposed to participate, such as the diversity of genetic background, VEGF-B isoforms or means for VEGF-B overproduction (recombinant proteins, naked plasmid DNA or adenoviral vectors).…”