Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

Abstract

A hallmark of proliferative retinopathies, such as retinopathy of prematurity (ROP), is a pathological neovascularization orchestrated by hypoxia and the resulting hypoxia-inducible factor (HIF)-dependent response. We studied the role of Hif2α in hematopoietic cells for pathological retina neovascularization in the murine model of ROP, the oxygen-induced retinopathy (OIR) model. Hematopoietic-specific deficiency of Hif2α ameliorated pathological neovascularization in the OIR model, which was accompanied by enhanced endothelial cell apoptosis. That latter finding was associated with up-regulation of the apoptosis-inducer FasL in Hif2α-deficient microglia. Consistently, pharmacological inhibition of the FasL reversed the reduced pathological neovascularization from hematopoietic-specific Hif2α deficiency. Our study found that the hematopoietic cell Hif2α contributes to pathological retina angiogenesis. Our findings not only provide novel insights regarding the complex interplay between immune cells and endothelial cells in hypoxia-driven retina neovascularization but also may have therapeutic implications for proliferative retinopathies.-Korovina, I., Neuwirth, A., Sprott, D., Weber, S., Sardar Pasha, S. P. B., Gercken, B., Breier, G., El-Armouche, A., Deussen, A., Karl, M. O., Wielockx, B., Chavakis, T., Klotzsche-von Ameln, A. Hematopoietic hypoxia-inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis.

Myeloid SOCS3 Deficiency Regulates Angiogenesis via Enhanced Apoptotic Endothelial Cell Engulfment

“…Efficient removal of damaged and/or dead cells by "professional phagocytes" such as microglia and macrophages is a critical process for maintaining tissue homeostasis. Several previous studies suggest that a close interplay between myeloid and vascular components exists in different settings that may involve inflammation, cell death, and clearance of dead cells [5,6,11,35]. Here, we demonstrate a role of SOCS3 in mononuclear phagocytes for the regulation of efferocytosis of apoptotic/dead endothelial cells, which can modulate ex vivo angiogenesis.…”

“…Multiple pathological situations accompanied by altered angiogenesis may display the rapid accumulation of cellular debris as well as activation of microglia/macrophages [6,10]. Recently, we could even show that mononuclear phagocytes can contribute to pathological retina angiogenesis by the modulation of endothelial cell apoptosis [11]. Subsequently, these mononuclear phagocytes may also contribute to the clearance of apoptotic endothelial cells.…”

A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

“…However, another group suggested that VEGF and HIF-2α in astrocytes may be essential for pathological neovascularization in their OIR model [ 47 ]. The other group demonstrated that hematopoietic HIF-2α deficiency could reduce pathological neovascularization through the modulation of endothelial cell death [ 48 ]. Therefore, we think that more comprehensive studies regarding HIF subtypes as well as VEGF-producing cell types and systemic vascular cell conditions may be needed for a better understanding of pathological mechanisms for ocular neovascularization.…”

Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

“…HIFs are heterodimers comprising two basic helix-loop-helix proteins (the HIFα and HIFβ subunits), which recognize the hypoxia response element (HRE, entailing the G/ACGTG motif) in the promoter of several genes, with major roles in different cell functions, including cellular metabolism, survival and proliferation, and in processes, such as angiogenesis, hematopoiesis and inflammation [17]. Whereas the expression of HIF1α protein is ubiquitous, the cellular expression of the HIF2α subunit is rather restricted to certain cells, for instance, cells of hematopoietic origin, ECs, adipocytes, glial cells and interstitial cells of the kidney [18,19,20,21,22,23]. While there is some functional overlap of both HIF isoforms, HIF1α and HIF2α also have distinct functions, each specifically regulating different genes.…”