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Experimental and clinical evidence indicate that bone marrow cells participate in the process of new blood vessel formation. However, the molecular mechanisms underlying their recruitment and their exact role are still elusive. Here, we show that bone marrow cells are recruited to the sites of neoangiogenesis through the neuropilin-1 (NP-1) receptor and that they are essential for the maturation of the activated endothelium and the formation of arteries in mice. By exploiting adeno-associated virus vector--mediated, long-term in vivo gene expression, we show that the 165-aa isoform of VEGF, which both activates the endothelium and recruits [NP-1.sup.+] myeloid cells, is a powerful arteriogenic agent. In contrast, neither the shortest [VEGF.sub.121] isoform, which does not bind NP-1 and thus does not recruit bone marrow cells, nor semaphorin 3A, which attracts cells but inhibits endothelial activation, are capable of sustaining arterial formation. Bone marrow myeloid cells are not arteriogenic per se nor are they directly incorporated in the newly formed vasculature, but they contribute to arterial formation through a paracrine effect ensuing in the activation and proliferation of tissue-resident smooth muscle cells., Introduction New blood vessel formation during postnatal life has been traditionally considered to arise through angiogenesis, a complex process essentially entailing the sprouting of new capillaries from preexisting vessels to [...]

Recovery from type 1 diabetes requires restoration or β-cell mass. We have shown that transgenic mice expressing insulin-like growth factor-I (IGF-I) in β-cells regenerate β-cell mass after diabetes induction (STZ). Vascularization plays a key role in the formation of pancreatic islets and increased vascularization in VEGF transgenic mice leads to increased β-cell mass. In basal conditions, expression of VEGF was 3.5-fold higher in IGF-I transgenic compared with control islets. However, the number of capillaries within the islets were similar in both groups of mice, indicating that angiogenesis was not increased. Expression of SDF-1, a chemo-attractant for bone marrow cells (BMC), was normal in non-diabetic conditions but increased after STZ-treatment. Therefore, we also investigated whether IGF-I expression in β-cells could increase BMC recruitment and differentiation into β-cells. To this end, BMC from β-actin/green fluorescent protein (GFP) transgenic mice were transplanted into lethally irradiated IGF-I transgenic mice. GFP+ cells with an hematopoietic phenotype (CD45+) were found in the interstitium of endocrine pancreatic tissue. In contrast, very few insulin+/GFP+ cells were detected in islets from these animals. Thus, IGF-I overexpression did not result in recruitment and differentiation of BMC into β-cells. Moreover, islets from STZ-treated bone marrow transplanted transgenic mice co-expressed IGF-I, suggesting that β-cells in such islets originated, probably by replicatiun, from pre-existing β-cells. Indeed, IGF-I expressing transgenic islets showed an increase in IRS2, total AKT, P-AKT, and P-FOXO 1 that lead to decreased levels of p27 mRNA inducing higher CDK4 expression, consistent with increased β-cell replication. These data suggest that IGF-I expression regenerates the endocrine pancreas during diabetes by B-cell replication rather than BMC differentiation. [ABSTRACT FROM AUTHOR]

An abstract of the article "The Formation of Stable and Mature Blood Vessels Requires the Proper Timing of VEGF Expression," by Sabrina Tafuro, Serena Zacchigna, Lorena Zentilin, Marina Dapas, and Mauro Giacca is presented.