Adenovirus encoding vascular endothelial growth factor–D induces tissue-specific vascular patterns in vivo

Abstract

The capacity of an adenovirus encoding the mature form of vascular endothelial growth factor (VEGF)–D, VEGF-DΔNΔC, to induce angiogenesis, lymphangiogenesis, or both was analyzed in 2 distinct in vivo models. We first demonstrated in vitro that VEGF-DΔNΔC encoded by the adenovirus (Ad-VEGF-DΔNΔC) is capable of inducing endothelial cell proliferation and migration and that the latter response is primarily mediated by VEGF receptor-2 (VEGFR-2). Second, we characterized a new in vivo model for assessing experimental angiogenesis, the rat cremaster muscle, which permits live videomicroscopy and quantitation of functional blood vessels. In this model, a proangiogenic effect of Ad-VEGF-DΔNΔC was evident as early as 5 days after injection. Immunohistochemical analysis of the cremaster muscle demonstrated that neovascularization induced by Ad-VEGF-DΔNΔC and by Ad-VEGF-A165 (an adenovirus encoding the 165 isoform of VEGF-A) was composed primarily of laminin and VEGFR-2–positive vessels containing red blood cells, thus indicating a predominantly angiogenic response. In a skin model, Ad-VEGF-DΔNΔC induced angiogenesis and lymphangiogenesis, as indicated by staining with laminin, VEGFR-2, and VEGFR-3, whereas Ad-VEGF-A165 stimulated the selective growth of blood vessels. These data suggest that the biologic effects of VEGF-D are tissue-specific and dependent on the abundance of blood vessels and lymphatics expressing the receptors for VEGF-D in a given tissue. The capacity of Ad-VEGF-DΔNΔC to induce endothelial cell proliferation, angiogenesis, and lymphangiogenesis demonstrates that its potential usefulness for the treatment of coronary artery disease, cerebral ischemia, peripheral vascular disease, restenosis, and tissue edema should be tested in preclinical models.

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

“…Signalling specificity can be determined by the duration and magnitude of Akt activation. In fact, the possibility of distinct and opposing short-term and long-term consequences of Akt activation in angiogenesis has been raised by several studies [27][28][29] . Moreover, other signalling molecules, such as ERK, also elicit distinct cellular outcomes depending on the duration and magnitude of their activation 30 .…”

Lymphangiogenesis by blind‐ended vessel sprouting is concurrent with hemangiogenesis by vascular splitting

“…As summarized in the Discussion, sprouting and nonsprouting modes of endogenous and VEGF-regulated hemangiogenesis following primordial vasculogenesis have been reported previously in other vascular remodeling contexts, particularly in developing mouse, quail, and chicken. Complex regulation of hemangiogenesis and lymphangiogenesis by the VEGF family is tissue-and program-specific (for example, Byzova et al, 2002), and much has been learned about VEGF cellular and molecular biology. Fundamental useful principles of VEGF-regulated blood and lymphatic vessel morphogenesis are also becoming more clear.…”

Akt1 governs breast cancer progression in vivo

“…Real-time PCR (31) and the pattern and density of microvessel immunostaining for von Willebrand was described in ref. 32. For ELISA, cells were seeded at 80% of confluence, and the growth medium was changed 24 h later to basal medium, containing 0.12% BSA after washing with PBS.…”