The capacity of inducing angiogenesis is a recognized hallmark of
cancer cells. The cancer microenvironment, characterized by
hypoxia and inflammatory signals, promotes proliferation, migration and activation of quiescent endothelial cells (EC) from surrounding vascular network. Current
anti-angiogenic drugs present side effects, temporary efficacy, and issues of primary resistance, thereby calling for the identification of new therapeutic targets. MICALs are a unique family of redox
enzymes that destabilize
F-actin in cytoskeletal dynamics. MICAL2 mediates Semaphorin3A-NRP2 response to VEGFR1 in rat ECs. MICAL2 also enters the p130Cas interactome in response to
VEGF in HUVEC. Previously, we showed that MICAL2 is overexpressed in metastatic
cancer. A small-molecule inhibitor of MICAL2 exists (CCG-1423). Here we report that 1) MICAL2 is expressed in neo-angiogenic ECs in human solid
tumors (kidney and
breast carcinoma,
glioblastoma and cardiac
myxoma, n = 67, were analyzed with immunohistochemistry) and in animal models of
ischemia/
inflammation neo-angiogenesis, but not in normal capillary bed; 2) MICAL2
protein pharmacological inhibition (
CCG-1423) or gene KD reduce EC viability and functional performance; 3) MICAL2 KD disables ECs response to
VEGF in vitro. Whole-genome gene expression profiling reveals MICAL2 involvement in angiogenesis and vascular development pathways. Based on these results, we propose that MICAL2 expression in ECs participates to
inflammation-induced neo-angiogenesis and that MICAL2 inhibition should be tested in
cancer- and noncancer-associated neo-angiogenesis, where chronic
inflammation represents a relevant pathophysiological mechanism.