Bone marrow cells recruited through the neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis in mice
Serena Zacchigna, … , Gianfranco Sinagra, Mauro Giacca
Serena Zacchigna, … , Gianfranco Sinagra, Mauro Giacca
Published May 15, 2008
Citation Information: J Clin Invest. 2008;118(6):2062-2075. https://doi.org/10.1172/JCI32832.
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Research Article Vascular biology

Bone marrow cells recruited through the neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis in mice

Abstract

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+ myeloid cells, is a powerful arteriogenic agent. In contrast, neither the shortest VEGF121 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.

Authors

Serena Zacchigna, Lucia Pattarini, Lorena Zentilin, Silvia Moimas, Alessandro Carrer, Milena Sinigaglia, Nikola Arsic, Sabrina Tafuro, Gianfranco Sinagra, Mauro Giacca

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Figure 6

A model to explain the role of BM cells in arteriogenesis.

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A model to explain the role of BM cells in arteriogenesis. Artery format...
Artery formation relies on the occurrence of 2 concomitant events, namely the activation of the local endothelium (through the canonical VEGF receptors) and the recruitment of BM-derived mononuclear cells through the NP-1 receptor; these cells in turn engage SMCs to the sites of endothelial activation. Only VEGF165 is able to stimulate both events and is thus arteriogenic. In contrast, VEGF121 activates the endothelium locally, thus inducing capillary sprouting, but is not able to bind NP-1, and thus it does not recruit BM cells nor does it form arteries. Finally, Sema3A, a high-affinity ligand for NP-1, is a potent recruiter of mononuclear cells from the BM, but it exerts an inhibitory effect on endothelial cells and therefore is not angiogenic.