Endothelium-Dependent Relaxation of Collateral Microvessels After Intramuscular Gene Transfer of Vascular Endothelial Growth Factor in a Rat Model of Hindlimb Ischemia

Abstract

Background —Recent investigations have demonstrated the ability of vascular endothelial growth factor (VEGF) to augment the development of collateral arteries in vivo. In vitro studies have suggested that the use of VEGF also improves the endothelium-dependent relaxation of collaterals at the microvascular level. The purpose of this study was to determine in vivo the extent to which vasomotor responses of collateral microvessels are altered after VEGF treatment. Methods and Results —Ischemia was induced in the hindlimb of 35 rats by excision of the femoral artery. Immediately thereafter, 400 μg of a plasmid encoding VEGF or β-galactosidase (control) was transfected into limb muscles. Four weeks later, synchrotron radiation microangiography, with a spatial resolution of 30 μm, was performed to document the reactivity of collateral microvessels. Administration of the endothelium-dependent vasodilator acetylcholine failed to induce dilation of collateral microvessels in control animals. By contrast, profound dilation of collaterals was observed after acetylcholine in VEGF-treated animals. This response was evident in vessels with a linear appearance but not in those with an undulating appearance. The resulting blood flow in the ischemic limb after administration of acetylcholine in the control animals was only 64.6±17.0% of that of the contralateral normal limb, whereas blood flow was augmented to 106.1±8.4% in VEGF-treated animals ( P <0.05). Conclusions —These results demonstrate in vivo that the use of VEGF restores impaired vasomotor responses in some types of collateral microvessels, which may help to provide a basis for understanding the microcirculation after therapeutic angiogenesis with VEGF.

Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep

“…11 and as a potential treatment for ischemic heart disease. [12][13][14] VEGF-A causes vasodilatation and an increase in blood flow in diverse animal blood vessels and vascular beds, 15,16 effects mediated partly through its ability to stimulate endothelial production of nitric oxide (NO) and prostacyclin. [17][18][19][20] The fall in utero-placental resistance in normal pregnancy is mediated by interstitial extravillous trophoblast secretion of angiogenic and vasodilator signals such as VEGF, to promote local blood flow to the uterus.…”

Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A165 in the uterine arteries of pregnant sheep

“…7 VEGF gene or protein therapy may prove therapeutically useful in local perivascular applications by stimulating vascular protective endothelial functions. 8 VEGF vasodilates and increases blood flow in diverse vascular beds, 9,10 the effects mediated partly through its stimulation of endothelial production of nitric oxide 11 and prostacyclin. 12 The fall in uteroplacental resistance in normal pregnancy is mediated by interstitial extravillous trophoblast secretion of angiogenic and vasodilatory factors such as VEGF, to promote local blood flow to the uterus.…”

High efficient adenoviral-mediated VEGF and Ang-1 gene delivery into osteogenically differentiated human mesenchymal stem cells

“…It was shown that gene transfer of VEGF expression plasmids induced neovascularization and brought significant increased blood flow with restored vasomotion in collateral vessels (Bauters et al, 1994;Asahara et al, 1996) as well as at the microvascular level (Takeshita et al, 1998). However, it remains unclear whether the administration of VEGF alone is adequate to promote the formation of mature vessels that are lined with pericytes or vascular smooth muscle cells.…”