  caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1 driven postischemic vasculogenesis; MARTINIVE, Philippe  ; et alin Circulation Research (2006) Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven postischemic vasculogenesis.Sbaa E, Dewever J, Martinive P, Bouzin C, Frérart F, Balligand JL, Dessy C ... [more ▼] Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven postischemic vasculogenesis.Sbaa E, Dewever J, Martinive P, Bouzin C, Frérart F, Balligand JL, Dessy C, Feron O. Unit of Pharmacology and Therapeutics, University of Louvain Medical School, Brussels, Belgium. When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the bone marrow. Caveolin, the structural protein of caveolae, was recently reported to directly influence the angiogenic process through the regulation of the vascular endothelial growth factor (VEGF)/nitric oxide pathway. In this study, using caveolin-1 null mice (Cav(-/-)), we examined whether caveolin was also involved in the EPC recruitment in a model of ischemic hindlimb. Intravenous infusion of Sca-1(+) Lin(-) progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization in Cav(-/-) mice, suggesting a defect in progenitor mobilization. The adhesion of Cav(-/-) EPC to bone marrow stromal cells indeed appeared to be resistant to the otherwise mobilizing SDF-1 (Stromal cell-Derived Factor-1) exposure because of a defect in the internalization of the SDF-1 cognate receptor CXCR4. Symmetrically, the attachment of Cav(-/-) EPC to SDF-1-presenting endothelial cells was significantly increased. Finally, EPC transduction with caveolin small interfering RNA reproduced this advantage in vitro and, importantly, led to a more extensive rescue of the ischemic hindlimb after intravenous infusion (versus sham-transfected EPC). These results underline the critical role of caveolin in ensuring the caveolae-mediated endocytosis of CXCR4, regulating both the SDF-1-mediated mobilization and peripheral homing of progenitor cells in response to ischemia. In particular, a transient reduction in caveolin expression was shown to therapeutically increase the engraftment of progenitor cells. PMID: 16601228 [PubMed - indexed for MEDLINE] [less ▲] Detailed reference viewed: 18 (2 ULg)Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles: implications for cancer treatment.; ; MARTINIVE, Philippe et alin Cancer Research (2004), 1(64), 3209-14 Although derived from the host tissue, the tumor vasculature is under the influence of the tumor microenvironment and needs to adapt to the resistance to blood flow inherent to the dynamics of tumor ... [more ▼] Although derived from the host tissue, the tumor vasculature is under the influence of the tumor microenvironment and needs to adapt to the resistance to blood flow inherent to the dynamics of tumor growth. Such vascular remodeling can offer selective targets to pharmacologically modulate tumor perfusion and thereby improve the efficacy of conventional anticancer treatments. Radiotherapy and chemotherapy can, indeed, take advantage of a better tumor oxygenation and drug delivery, respectively, both partly dependent on the tumor blood supply. Here, we showed that isolated tumor arterioles mounted in a pressure myograph have the ability, contrary to size-matched healthy arterioles, to contract in response to a transluminal pressure increase. This myogenic tone was exquisitely dependent on the endothelin-1 pathway because it was completely abolished by the selective endothelin receptor A (ETA) antagonist BQ123. This selectivity was additionally supported by the large increase in endothelin-1 abundance in tumors and the higher density of the ETA receptors in tumor vessels. We also documented by using laser Doppler microprobes and imaging that administration of the ETA antagonist led to a significant increase in tumor blood flow, whereas the perfusion in control healthy tissue was not altered. Finally, we provided evidence that acute administration of the ETA antagonist could significantly stimulate tumor oxygenation, as determined by electron paramagnetic resonance oximetry, and increase the efficacy of low-dose, clinically relevant fractionated radiotherapy. Thus, blocking the tumor-selective increase in the vascular endothelin-1/ETA pathway led us to unravel an important reserve of vasorelaxation that can be exploited to selectively increase tumor response to radiotherapy. [less ▲] Detailed reference viewed: 2 (0 ULg) |
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