VASCULAR BIOLOGY Conditional HIF-1 induction produces multistage neovascularization with

Neovascularization is a crucial compo-nent of tumor growth and ischemia. Al-though prior work primarily used disease models, delineation of neovasculariza-tion in the absence of disease can reveal intrinsic mechanisms of microvessel regulation amenable to manipulation in illness. We created a conditional model of epithelial HIF-1 induction in adult mice (TetON-HIF-1 mice). Longitudinal photoa-coustic microscopy (L-PAM) was coinci-dentally developed for noninvasive, label-free serial imaging of red blood cell-perfused vasculature in the same mouse for weeks to months. TetON-HIF-1 mice evidenced 3 stages of neovasculariza-tion: development, maintenance, and transgene-dependent regression. Regres-sion occurred despite extensive and tight pericyte coverage. L-PAM mapped micro-vascular architecture and quantified volu-metric changes in neocapillary morpho-genesis, arteriovenous remodeling, and microvessel regression. Developmental stage endothelial proliferation down-regulation was associated with a DNA damage checkpoint consisting of p53, p21, and endothelial -H2AX induction. The neovasculature was temporally re-sponsive to VEGFR2 immuno-blockade, with the developmental stage sensitive, and the maintenance stage resistant, to DC101 treatment. L-PAM analysis also pinpointed microvessels ablated or resistant to VEGFR2 immuno-blockade. HIF-1–recruited myeloid cells did not mediate VEGFR2 inhibitor resistance. Thus, HIF-1 neovascularization in the absence of disease is self-regulated via cell autonomous endothelial check-points, and resistant to angiogenesis inhibitors independent of myeloid cells. (Blood. 2011;117(15):4142-4153