Although the sKitL/SDF1 axis appears as critical for hematopoietic stem cell mobilization, the roles of other cytokines should however not be neglected and among them is the prototypical angiogenic growth factor, namely VEGF.
Isner and colleagues reported for the first time an increase in circulating endothelial progenitor cells (EPC) following VEGF administration in vivo . VEGF-induced mobilization of bone marrow-derived EPC was shown to lead to increased differentiated EPC in vitro and augmented corneal neovascularization in vivo. In an attempt to further define the role of VEGF in the regulation of postnatal hematopoiesis and vasculogenesis, injections of recombinant protein or adenoviral vectors expressing soluble 165-kDa VEGF or matrix-bound 189-kDa VEGF were evaluated. 165-kDa VEGF, but not 189-kDa VEGF, induced a rapid mobilization of VEGFR-2+ EPC . Neutralizing monoclonal antibody to the VEGF receptor type VEGFR2 completely inhibited the 165-kDa-VEGF-induced mobilization. Interestingly, investigators exploring the relationship between exercise and EPC mobilization in ischemic patients, found a direct correlation between increased plasma VEGF levels and increased circulating EPC in these patients .
From the cancer field also, a large body of evidence plead for a direct role of VEGF in progenitor cell mobilization. Tumor angiogenesis is indeed associated, although to various extents, with recruitment of hematopoietic and circulating endothelial precursor cells. One of the most elegant demonstration is from Lyden and colleagues who documented by using the angiogenic-defective tumor-resistant Id-mutant mice, that VEGF-mobilized stem cells (from a wild-type donor) could restore tumor angiogenesis and growth . Interestingly, double targeting of both VEGF receptors, VEGFR1 and VEGFR2, was needed to abrogate tumor growth, suggesting the probable multiplicity of bone marrow-derived cell types involved in tumor vasculogenesis.
Altogether, the above findings established a role for VEGF in postnatal neovascularization which complements its known impact on angiogenesis. The place of VEGF downstream or upstream sKitL and SDF-1 is unclear and probably depends on specific pathophysiological contexts. The relationship with matrix metallopro-teinases (MMPs) also is multiple. For instance, MMP may promote the release of extracellular matrix-bound or cell-surface-bound VEGF but MMPs can also play key roles as necessary intermediates downstream of VEGF. Accordingly, mobilization of hematopoietic progenitors in response to VEGF was found markedly impaired in MMP-9-/- mice .
Further dissection of the VEGF signaling also led to the identification of two additional mediators of the progenitor cell mobilization, namely the endothelial nitric oxide synthase and caveolin. These two intermediaries will be discussed under the next two headings.
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