Vascular Endothelial Growth Factor-B Acts as a Coronary Growth Factor in Transgenic Rats Without Inducing Angiogenesis, Vascular Leak, or Inflammation

Abstract

Background— Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood. Methods and Results— Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B 167 isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment. Conclusions— VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B–induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B–induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

“…Mechanistically, VEGF-B increased phosphorylation of ERK1/2, a downstream mediator of VEGF receptor signaling in the heart, and ribosomal protein S6, indicating activation of the mTORC1 pathway. The effect of VEGF-B is consistent with our previous studies, in which VEGF-B induced mild cardiac and cardiomyocyte hypertrophy that was not converted to cardiomyopathy even upon prolonged VEGF-B overexpression (10,11). This may be because VEGF-B-induced cardiomyocyte hypertrophy is based on enhanced signaling by endogenous VEGF via endothelial VEGFR2, leading to a concomitant increase of the coronary vasculature (11).…”

“…Importantly, although VEGF-B inhibited DOX-induced whole-body wasting in all experiments, it did not increase body weight in healthy mice without cachexia, as we have reported previously (10,11). Mechanistically, VEGF-B increased phosphorylation of ERK1/2, a downstream mediator of VEGF receptor signaling in the heart, and ribosomal protein S6, indicating activation of the mTORC1 pathway.…”

“…ERK signaling is an important mediator of angiogenesis and arteriogenesis downstream of VEGFR2 activation, and VEGF-B increases ERK1/2 phosphorylation in the heart (10,18). Here were found that DOX treatment significantly reduced ERK1/2 phosphorylation, which was reversed by VEGF-B (Fig.…”

“…The highest endogenous concentrations of VEGF-B are found in cardiomyocytes (9). Exogenous VEGF-B is a potent arteriogenic growth factor that can promote physiological cardiac hypertrophy and counteract metabolic problems of obesity (10)(11)(12). Furthermore, reduced VEGF-B expression occurs in dilated cardiomyopathy and…”

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

“…We have reported that this right ventricle (RV) capillary rarefaction is associated with a decreased myocardial expression of VEGF-A. 35 Now we show that the expression of the VEGF-B splice variant [36][37][38] is likewise decreased in the tissues of failing rat RVs, further supporting the hypothesis that loss of expression of angiogenesis factors can explain the capillary rarefaction 35,39 in failing RVs. 34 …”