Endothelial Progenitor Cells Induce a Phenotype Shift in Differentiated Endothelial Cells towards PDGF/PDGFRβ Axis-Mediated Angiogenesis

Abstract

BackgroundEndothelial Progenitor Cells (EPC) support neovascularization and regeneration of injured endothelium both by providing a proliferative cell pool capable of differentiation into mature vascular endothelial cells and by secretion of angiogenic growth factors.ObjectiveThe aim of this study was to investigate the role of PDGF-BB and PDGFRβ in EPC-mediated angiogenesis of differentiated endothelial cells.Methods and ResultsConditioned medium from human EPC (EPC-CM) cultured in hypoxic conditions contained substantially higher levels of PDGF-BB as compared to normoxic conditions (P<0.01). EPC-CM increased proliferation (1.39-fold; P<0.001) and migration (2.13-fold; P<0.001) of isolated human umbilical vein endothelial cells (HUVEC), as well as sprouting of vascular structures from ex vivo cultured aortic rings (2.78-fold increase; P = 0.01). The capacity of EPC-CM to modulate the PDGFRβ expression in HUVEC was assessed by western blot and RT-PCR. All the pro-angiogenic effects of EPC-CM on HUVEC could be partially inhibited by inactivation of PDGFRβ (P<0.01). EPC-CM triggered a distinct up-regulation of PDGFRβ (2.5±0.5; P<0.05) and its phosphorylation (3.6±0.6; P<0.05) in HUVEC. This was not observed after exposure of HUVEC to recombinant human PDGF-BB alone.ConclusionThese data indicate that EPC-CM sensitize endothelial cells and induce a pro-angiogenic phenotype including the up-regulation of PDGFRβ, thereby turning the PDGF/PDGFRβ signaling-axis into a critical element of EPC-induced endothelial angiogenesis. This finding may be utilized to enhance EPC-based therapy of ischemic tissue in future.

Factors Secreted by Mesenchymal Stem Cells and Endothelial Progenitor Cells Have Complementary Effects on Angiogenesis In Vitro

“…These findings were in accordance with the hypothesis that stem cells with long-term engraftment capabilities were predominantly located at the lowest end of an oxygen gradient in the bone marrow, in hypoxic regions containing sinusoids rather than capillary structures [21]. Other studies have shown that stem cells were resistant to hypoxia-induced apoptosis [14], and hypoxia induced the production and secretion of factors that stimulate inflammation and neovascularization [22,23]. The present study confirmed the hypoxia-resistance of MSCs and showed the partial preservation of their innate properties in hypoxic versus normoxic cells.…”

NOTCH3 regulates stem-to–mural cell differentiation in infantile hemangioma

“…PDGFRβ expression has also been noted in the angiogenic ECs in glioblastoma multiforme (39). Furthermore, blocking PDGFRβ in HUVECs blunted the angiogenic response induced by endothelial progenitor cell-conditioned media (40). Thus, misexpression of PDGFRβ in HemECs may contribute to the increased proliferation in HemECs and abnormal angiogenesis in IH.…”

A Novel Cell Adhesion Region in Tropoelastin Mediates Attachment to Integrin αVβ5

“…In additional, integrin ␣ V ␤ 5 promotes angiogenesis via a pathway that is distinct from integrin ␣ V ␤ 3 -dependent angiogenesis. Integrin ␣ V ␤ 5 is also essential for the differentiation of endothelial progenitors to differentiated endothelial cells (34,35). Therefore, further investigation of integrin ␣ V ␤ 5 -tropoelastin interactions could lead us to a better understanding of these disease and physiological states.…”