Myeloid cells play a key role in ocular neovascularization, which is a pathological feature of the common sight-threatening eye diseases retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and age-related macular degeneration (AMD). Myeloid cells can either promote or protect against ocular neovascularization, depending on the timing of intervention and specific cell population. Depletion of macrophages by clodronate reduces retinal neovascularization in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) [
1,
2]. However, injection of myeloid precursors reduces retinal neovascularization and enhances vascular repair in OIR [
3,
4]. We have previously shown that myeloid-derived VEGF production is not an essential requirement for ocular neovascularization [
5], in contrast to other pathological conditions such as tumor growth [
6]. Nor does deletion in myeloid cells of the genes encoding hypoxia-inducible factors HIF1α and HIF2α, which are strong activators of VEGF expression [
7,
8], have an impact on ocular neovascularization [
5]. Von Hippel–Lindau tumor suppressor protein (pVHL) targets HIF factors for rapid proteosomal degradation in normoxic conditions and in its absence their stabilization activates the HIF pathway [
9,
10]. Both HIF1α and HIF2α isoforms are stabilized in the inner retina during the hypoxic phase of OIR with distinct cellular distributions [
11]; despite their close structural homology, HIF1α and HIF2α act differentially during both development and hypoxia. Activation of the HIF pathway in astrocytes and neurons by deletion of
Vhl is proangiogenic in the postnatal retina [
12,
13], but in OIR systemic pharmacological activation of HIFs protects against retinal vasoregression and subsequent pathological neovascularization [
14]. Here, we sought to determine the specific responses of myeloid cells to stabilization of HIF isoforms in retinal ischemia and to establish the impact on retinal vasculature. We did so by investigating OIR in mice with myeloid cell-specific deletion of
Vhl,
Hif1a, and/or
Epas1 (encoding HIF2α). We found that stabilization of both HIF1α and HIF2α in myeloid cells by
Vhl deletion promotes expression of VEGF and bFGF and enhances retinal vascular regeneration in association with improved density and organization of the astrocytic network.