Reevaluation of the Role of VEGF-B Suggests a Restricted Role in the Revascularization of the Ischemic Myocardium

Abstract

Objective— The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. Methods and Results— We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B −/− ) or overexpressing VEGF-B 167 . After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B 167 overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B 167 overexpression failed to enhance vascular growth in the skin or ischemic limb. Conclusion— VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.

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

“…63 , 69 Gene knockout studies showed that VEGF-B does participate in coronary vasculature development and normal physiological responses to ischemia and vascular occlusion. 18 And, the HF patients showed the declined VEGF-B, 70 both in ischemic and dilated cardiomyopathy. Mice lacking VEGF-B displayed mild cardiac phenotypes, such as the slightly smaller heart and dysfunctional coronary vasculature in Bellomo VEGF-B −/− mice 67 and a prolonged PQ interval in Aase VEGF-B −/− mice.…”

“…Subsequent studies, however, argued against the angiogenic activity of this molecule. 15-18 Physiologically, VEGF-B has little growth effects, as demonstrated in gain-of-function studies using transgenic 15 and adenoviral 16 expression of VEGF-B models and loss-of-function studies using VEGF-B null mice. 17 , 18 Under pathological conditions, this molecule can prevent cells from apoptosis and death.…”

“…15-18 Physiologically, VEGF-B has little growth effects, as demonstrated in gain-of-function studies using transgenic 15 and adenoviral 16 expression of VEGF-B models and loss-of-function studies using VEGF-B null mice. 17 , 18 Under pathological conditions, this molecule can prevent cells from apoptosis and death. It showed both survival effect in laser injury-induced choroidal neovascularization or ischemia-originated retinal neovascularization models, 19 cardiac ischemia mouse, 20 and neuron-protective effect for the brain cortical neurons and retinal neurons 21 and motor neurons in the spinal cord.…”

“…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). 89 In this respect, adenoviruses and AAV vectors administration represented the most efficient vectors to transfer genes into the adult myocardium and ensured a prolonged effect.…”

“…95 In comparison, the VEGF-B has marked superiority over its family members. First, VEGF-B showed high selectivity to stimulate angiogenesis, especially in the ischemic myocardium, 18 being expected to stimulate angiogenic without causing adverse effects. The upregulation of VEGF-B levels in the ischemic heart but not in the ischemic muscle might partly account for its specificity.…”