VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells

Abstract

Adult neovascularization relies on the recruitment of circulating cells, but their angiogenic roles and recruitment mechanisms are unclear. We show that the endothelial growth factor VEGF is sufficient for organ homing of circulating mononuclear myeloid cells and is required for their perivascular positioning and retention. Recruited bone marrow-derived circulating cells (RBCCs) summoned by VEGF serve a function distinct from endothelial progenitor cells. Retention of RBCCs in close proximity to angiogenic vessels is mediated by SDF1, a chemokine induced by VEGF in activated perivascular myofibroblasts. RBCCs enhance in situ proliferation of endothelial cells via secreting proangiogenic activities distinct from locally induced activities. Precluding RBCCs strongly attenuated the proangiogenic response to VEGF and addition of purified RBCCs enhanced angiogenesis in excision wounds. Together, the data suggest a model for VEGF-programmed adult neovascularization highlighting the essential paracrine role of recruited myeloid cells and a role for SDF1 in their perivascular retention.

Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy

“…Our results suggest that a similar process can also occur independently of tumor with drug-induced up-regulation of multiple proangiogenic growth factors. In this regard, a number of studies have shown that angiogenesis can be induced or amplified by G-CSF (18), SCF (19), SDF-1␣ (20), and osteopontin (21), by diverse mechanisms, including mobilization of circulating bone-marrow-derived proangiogenic cell populations (22), such as endothelial progenitor cells (23). Such effects could conceivably contribute to the rapid vascular ''rebound'' in mouse tumors observed within 1 week of terminating therapy with an RTKI similar in nature to sunitinib (16), results that could clearly have implications for whether a continuous vs. discontinuous schedule of treatment using such drugs would be superior.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…CXCL12 and VEGF are also suggested to act as chemoattractants for myeloid cells [222,223] and may act in concert for recruiting neutrophil to the tumor microenvironment. Under normal conditions, a tight cooperation between myeloid cells and endothelial progenitor cells is required for proper neovascularization [223].…”

“…Under normal conditions, a tight cooperation between myeloid cells and endothelial progenitor cells is required for proper neovascularization [223]. VEGF induces bone marrow-derived myeloid cell mobilization to the circulation and through VEGF-mediated upregulation of SDF1/CXCL12 in activated perivascular myofibroblasts, the myeloid cells are kept in close proximity to angiogenic vessels [223]. VEGF is upregulated in a wide variety of tumors [69,[224][225][226][227], as is CXCL12 [228].…”

“…VEGF is upregulated in a wide variety of tumors [69,[224][225][226][227], as is CXCL12 [228]. CXCL12, that is also upregulated by hypoxia [229], augments CXCR4 expression on vascular endothelial cells [230] and attracts CXCR4 + cells, including neutrophils, to the tumor [223].…”

My O'Myeloid, a tale of two lineages

“…To this end, there seem to exist multiple schools of thought. One suggests that bone marrow-derived hematopoietic cells home to areas of vascular injury and settle in close approximation to the newly forming vasculature, contributing to angiogenesis via secretion of important cytokines for endothelial proliferation and recruitment (18,19). A second proposes that bone marrow-derived endothelial progenitor cells (EPCs), the definition of which remains elusive (20), are able to directly participate in angiogenesis (21,22 (Fig.…”