EMILIN 2 AS A REGULATOR OF VASCULAR EFFICIENCY

Abstract

EMILIN2 is an extracellular matrix component that, due to its multimodular domains exerts multifaceted roles in the tumor microenvironment, overall exercising a suppressive function. Recently, we have shown that EMILIN2 promotes angiogenesis through the direct binding to epidermal growth factor receptor (EGFR) and the consequent activation of interleukin-8 (IL-8) production. In turn, IL-8 stimulates the proliferation and migration of endothelial cells (EC). Exploiting the Emilin-2-/- mouse models we demonstrated that the absence of EMILIN2 resulted in down-modulation of EGFR signaling pathway thus hampering the formation of both normal and tumor-associated vessels. Furthermore, also the efficiency of the vessels formed in the absence of EMILIN2 was impaired since vessel perfusion was lower in Emilin-2-/- mice. As a consequence, low levels EMILIN2 associated with poor drug delivery and efficacy. However, this effect was not linked to the impaired activation of EGFR. Immunofluorescence analyses revealed that the absence of EMILIN2 compromised the recruitment of pericytes along the blood vessels, which we hypothesized could be accountable for the loss of vascular efficiency observed in Emilin-2-/- mice. In agreement with this hypothesis we demonstrated that EMILIN2 acts as a chemotactic stimulus and serves as an adhesion substrate for perycites. These two functions rely on the engagement of integrin α5β1 and α6β1, highly expressed by pericytes. Furthermore, EMILIN2-challenged ECs increase the expression of PDGF, a key cytokine for pericyte recruitment. Taken together, these results suggest that EMILIN2 is a key regulator of pericyte recruitment and vascular stability and we envision that the analysis of EMILIN2 expression may serve to predict the efficacy of cancer therapy.