Blockade of Vascular Endothelial Growth Factor Suppresses Experimental Restenosis After Intraluminal Injury by Inhibiting Recruitment of Monocyte Lineage Cells

Abstract

Background— Therapeutic angiogenesis by delivery of vascular endothelial growth factor (VEGF) has attracted attention. However, the role and function of VEGF in experimental restenosis (neointimal formation) after vascular intraluminal injury have not been addressed. Methods and Results— We report herein that blockade of VEGF by soluble VEGF receptor 1 ( sFlt-1 ) gene transfer attenuated neointimal formation after intraluminal injury in rabbits, rats, and mice. sFlt-1 gene transfer markedly attenuated the early vascular inflammation and proliferation and later neointimal formation. sFlt-1 gene transfer also inhibited increased expression of inflammatory factors such as monocyte chemoattractant protein-1 and VEGF. Intravascular VEGF gene transfer enhanced angiogenesis in the adventitia but did not reduce neointimal formation. Conclusions— Increased expression and activity of VEGF are essential in the development of experimental restenosis after intraluminal injury by recruiting monocyte-lineage cells.

Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

“…Emerging evidence indicates that VEGF plays a critical role in host inflammatory responses in several disease states, including atherosclerosis (7,12,18,21,23,25,39,40), sepsis (37), acute lung injury (15), and rheumatoid arthritis (11). These data indicate that besides the proangiogenic activity, VEGF has a potent proinflammatory property, although the underlying mechanism is largely unclear.…”

Vasa Vasorum in Normal and Diseased Arteries

“…Conversely, inhibition of growth factor signaling reduced it. [78][79][80] Microcomputed tomography imaging further demonstrates a direct correlation between the computed tomography-determined extent of adventitial angiogenesis and the extent of neointima. 19,81 Thus, there is a strong correlation between the extent of the adventitial vasculature and the extent of neointima formation.…”

Endogenous Inhibitors of Angiogenesis

“…Therefore, VEGF can circulate in a bound state (bound to sFlt-1) as well as in free state depending on the amount of sFlt-1 in the circulation. In this regard, several reports have suggested that sFlt-1 can serve as an antitumor agent by inhibiting VEGF (130)(131)(132). The relevance for sFlt-1 at the normal physiologic concentration in the regulation of cancer progression is not understood.…”