Vascular Endothelial Growth Factor-C (VEGF-C/VEGF-2) Promotes Angiogenesis in the Setting of Tissue Ischemia

Abstract

Recently , vascular endothelial growth factor-C (VEGF-C or VEGF-2) was described as a specific ligand for the endothelial receptor tyrosine kinases VEGFR-2 and VEGFR-3. In vivo data , limited to constitutive overexpression in transgenic mice , have been interpreted as evidence that the growth-promoting effects of VEGF-C are restricted to development of the lymphatic vasculature. The current studies were designed to test the hypothesis that constitutive expression of VEGF-C in adult animals promotes angiogenesis. In vitro, VEGF-C exhibited a dose-dependent mitogenic and chemotactic effect on endothelial cells , particularly for microvascular endothelial cells (72% and 95% potency , respectively , compared with VEGF-A/ VEGF-1). VEGF-C stimulated release of nitric oxide from endothelial cells and increased vascular permeability in the Miles assay; the latter effect was attenuated by pretreatment with the nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester. Both VEGFR-2 and VEGFR-3 receptors were shown to be expressed in human saphenous vein and internal mammary artery. The potential for VEGF-C to promote angiogenesis in vivo was then tested in a rabbit ischemic hindlimb model. Ten days after ligation of the external iliac artery , VEGF-C was administered as naked plasmid DNA (pcVEGF-C; 500 g) from the polymer coating of an angioplasty balloon (n ‫؍‬ 8 each) or as recombinant human protein (rhVEGF-C; 500 g) by direct intra-arterial infusion. Physiological and anatomical assessments of angiogenesis 30 days later showed evidence of therapeutic angiogenesis for both pcVEGF-C and rhVEGF-C. Hindlimb blood pressure ratio (ischemic/normal) after pcVEGF-C increased to 0.83 ؎ 0.03 after pcVEGF-C versus 0.59 ؎ 0.04 (P < 0.005) in pGSVLacZ controls and to 0.76 ؎

Concurrent Induction of Lymphangiogenesis, Angiogenesis, and Macrophage Recruitment by Vascular Endothelial Growth Factor-C in Melanoma

“…16 VEGF-C was also 50-to 100-fold less potent than VEGF in inducing proliferation of bovine capillary endothelial cells, 10,16 human umbilical vein endothelial cells, or lung microvascular endothelial cells in vitro. 11,19 In contrast, VEGF-C promoted proliferation of human dermal microvascular endothelial cells with a similar potency as VEGF, 17 suggesting that microvascular endothelial cells derived from the skin blood vessels may be more responsive to VEGF-C than endothelial cells from other tissues. Moreover, VEGF-C acted synergistically with VEGF on in vitro angiogenesis, 17,61 suggesting that in VEGF-C-expressing melanomas VEGF-C may act in cooperation with VEGF to increase vascular permeability and angiogenesis.…”

“…VEGF-C was originally described as a specific growth factor for lymphatic vessels 12,13 but was later also found to induce angiogenesis of blood vessels, 18,19 raising a question about the mechanisms that determine the distinct effects of VEGF-C in vivo. As demonstrated in vitro, the secreted 31-kd VEGF-C protein predominantly activates VEGFR-3 whereas the mature, fully processed 21-kd form also activates VEGFR-2, suggesting that the biological functions of VEGF-C may be regulated by differential proteolytic processing.…”

“…10,15 Indeed, VEGF-C stimulates the proliferation and migration of blood vascular endothelial cells in vitro and has been shown to increase vascular permeability in the Miles assay, 10,11,16,17 and to induce angiogenesis in the mouse corneal micropocket assay and in the rabbit ischemic hind limb model. 18,19 VEGF-C mRNA expression has been demonstrated in a large number of human tumors, including malignant melanomas. 20 -32 Expression of its receptor VEGFR-3 has been detected in lymphatic vessels and occasionally also in blood vessels adjacent to cancer cells.…”

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…VEGF-B is a pro-angiogenic growth factor, which is constitutively expressed in cerebral microvessels and plays a role only in the maintenance of the microcirculatory network (Nag et al 2002) and adaptation to ischemic challenges (Bellomo et al 2000). Among other members of the VEGF, family expression of Vegfc (Witzenbichler et al 1998) was unchanged, whereas expression of Vegfd (Cfos-induced growth factor/FIGF) (Debinski et al 2001) was down-regulated by IGF-1 deficiency. Expression of platelet-derived growth factor (Pdgfβ) (He et al 2015) and fibroblast growth factors-1 and −2 (Fgf-1, Fgf-2) was unaltered by either IGF-1 deficiency and hypertension, whereas expression of connective tissue growth factor (Ctgf) was up-regulated in hypertensive IGF-1 deficient mice.…”

Serum markers of angiogenesis and myocardial ultrasonic tissue characterization in patients with dilated cardiomyopathy

“…Their study showed the reduced mRNA and protein levels of myocardial VEGF-A in transplant patients with end-stage DCM, whereas elevated both expression levels of VEGF-C have been shown. A previous experimental report has shown that VEGF-C promotes angiogenesis and augments flow to ischemic tissues in the setting of tissue ischemia [31]. Therefore, changes on VEGF levels in serum of DCM patients may result from an increase of myocardial VEGF-C rather than a decrease in VEGF-A.…”