Vascular endothelial growth factor-D transgenic mice show enhanced blood capillary density, improved postischemic muscle regeneration, and increased susceptibility to tumor formation

Abstract

Vascular endothelial growth factor-D (VEGF-D) has angiogenic and lymphangiogenic activity, but its biologic role has remained unclear because knockout mice showed no clear phenotype. Transgenic (TG) mice expressing the mature form of human VEGF-D (hVEGF-D) were produced by lentiviral (LV) transgenesis using the perivitelline injection method. Several viable founders showed a macroscopically normal phenotype and the transgene transmitted through germ line. Expression of hVEGF-D mRNA was high in skeletal muscles, skin, pancreas, heart, and spleen. A significant increase was found in capillary density of skeletal muscles and myocardium, whereas no changes were observed in lymphatic capillary density. After induction of hindlimb ischemia, the TG mice showed enhanced capacity for muscle regeneration. However, on aging the TG mice had significantly increased mortality from malignant tumors, of which half were breast adenocarcinomas characterized with the absence of periductal muscle cells. Some tumors metastasized into the lungs. In addition, lung and skin tumors were found, but no blood-or lymphatic vesselderived malignancies were detected. We conclude that in mice hVEGF-D is an angiogenic factor associated with improved muscle regeneration after ischemic injury but also with increased incidence of tumor formation with a preference for mammary gland tumors.

Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors

“…3), were found with gel/VEGF delivery. These results are consistent with past reports that VEGF may play an important role in muscle maintenance and regeneration (17)(18)(19). The contractile properties of the injured muscle (Fig.…”

“…Sustained VEGF delivery alone from alginate gels had a significant impact on angiogenesis and tissue perfusion but a less pronounced effect on muscle regeneration (17)(18)(19). These results are in accord with previous reports that the sustained and controlled release of VEGF from both a poly(lactide-co-glicolide) (PLG) (15) and the same injectable alginate-based vehicle (16) stimulated angiogenesis, returned perfusion to normal levels, and prevented necrosis in ischemic hindlimbs.…”

“…The sustained release of VEGF from polymeric delivery systems has been widely implicated in neovascularization and was previously demonstrated to enhance blood vessel formation and perfusion within ischemic muscle tissue (15,16). Several recent studies have demonstrated that VEGF leads to better maintenance of skeletal muscle tissue in mouse models of muscular dystrophy, suggesting that VEGF may also play a role in muscle regeneration after injury (17)(18)(19). Other findings highlight the possibility that VEGF's ability to promote vascularization could increase the availability of blood vessel-associated stem cells capable of participating in muscle regeneration (20)(21)(22).…”

Vegf-B

“…VEGF-B transgenic expression in different organs induces no or minimum angiogenesis. Transgenic expression of all the other VEGF family members, such as VEGF-A, [38][39][40] PlGF, 41 VEGF-C, 42 VEGF-D 43 or VEGF-E, 44 induced either angiogenesis or lymphangiogenesis. VEGF-B is the only member of the VEGF family, transgenic overexpression of which in different organs did not induce angiogenesis or lymphangiogenesis.…”

Can VEGF-B Be Used to Treat Neurodegenerative Diseases?

“…In contrast to VEGF-A and PlGF, VEGF-B is not required for neovessel formation in proliferative retinopathy (Reichelt et al, 2003) or blood vessel remodeling in pulmonary hypertension (Louzier et al, 2003). Transgenic expression of all the other VEGF family members, such as VEGF-A (Detmar et al, 1998;Larcher et al, 1998;Xia et al, 2003), PlGF (Odorisio et al, 2002), VEGF-C , VEGF-D (Karkkainen et al, 2009) or VEGF-E (Kiba et al, 2003) induced either angiogenesis or lymphangiogenesis. VEGF-B is the only member of the VEGF family, transgenic overexpression of which in different organs did not induce angiogenesis or lymphangiogenesis (Karpanen et al, 2008;Mould et al, 2005).…”