The main regulator of neovascularization is Vascular Endothelial Growth Factor (VEGF). We recently demonstrated that QK, a de novo engineered VEGF mimicking peptide, shares in vitro the same biological properties of VEGF, inducing capillary formation and organization. On these grounds, the aim of this study is to evaluate in vivo the effects of this small peptide. Therefore, on Wistar Kyoto rats, we evaluated vasomotor responses to VEGF and QK in common carotid rings. Also, we assessed the effects of QK in three different models of angiogenesis: ischemic hindlimb, wound healing and Matrigel plugs. QK and VEGF present similar endothelium-dependent vasodilatation. Moreover, the ability of QK to induce neovascularization was confirmed us by digital angiographies, dyed beads dilution and histological analysis in the ischemic hindlimb as well as by histology in wounds and Matrigel plugs. Our findings show the proangiogenic properties of QK, suggesting that also in vivo this peptide resembles the full VEGF protein. These data open to new fields of investigation on the mechanisms of activation of VEGF receptors, offering clinical implications for treatment of pathophysiological conditions such as chronic ischemia.
Increased levels of G protein coupled receptor kinase GRK2 appear to participate in hypertension presumably through the desensitization of β adrenergic receptors (βARs) that mediate vasodilatation. There are contrasting data on the occurrence of βAR desensitization in the vasculature, we therefore investigated βAR vasodilatation and desensitization in normotensives and in hypertensive humans. In blood lymphocytes, we assessed βAR signaling and GRK2 expression and found βAR signaling alterations and, consistent with desensitization, increased GRK2 levels in hypertensives. We studied in vivo vasodilatation to the βAR agonist isoproterenol (ISO) injected in the brachial artery in control conditions and during the concomitant infusion of heparin, a known in vitro nonspecific GRK inhibitor. ISO induced a dose-dependent vasorelaxation that was attenuated in hypertensives indicating a loss of βAR signaling. Intra-arterial infusion of heparin inhibited lymphocyte GRK2 activity and prevented desensitization of βAR vasodilatation in normotensives. In hypertensives, heparin restored vasodilatation to ISO, to levels observed in normotensives. Our results suggest that βAR desensitization does indeed occur at the vascular levels in vivo, and that heparin by acting as a GRK inhibitor prevents this in normotensives and restores impaired βAR vasodilation in hypertensives. We conclude that desensitization participates to impaired βAR vasodilation in hypertension.
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