NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy (NATURE COMMUNICATIONS 2018, 9:3463 )

報告日期: 2019/11/26
報告時間: 17:10/18:00
報告學生: 饒師維
講評老師: 張義昇
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NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy

Dubrac A, Künzel SE, et al. Nature Communications. 2018; 9: 3463.

SpeakerShih-Wei Jao (饒師維)                              Time2019/11/26, 17:10-18:00

CommentatorAP. Yi-Sheng Chang (張義昇)           PlaceRoom 602

Abstract

Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) were retinal diseases associated with neovascularization. ROP is characterized by chronic ischemia that promotes the formation of pathological neovascular tuft (NVT). In the retina, abnormal angiogenesis causes vitreous hemorrhage and tractional retinal detachment, leading to blindness. Pericytes are multi-functional mural cells that wrap the microvascular endothelial cells (EC). The function of pericytes helps stabilizing the vessel wall, sprouting, and preventing vascular leakage. The recruitment of pericytes in the developing vessel is regulated by the release of platelet-derived growth factor B (PDGF-B) by EC. Previous studies showed that the knockdown or over-expression of PDGF-B led to decreased or increased retinal vessel formation, respectively. This study investigated the role of pericytes and PDGFR-β downstream signaling in oxygen-induced retinopathy (OIR) mice, a model of ROP. In the first part of this paper, immunostaining with pericyte marker (NG2, PDGFRβ, DESMIN, and α-SMA) and the smooth muscle markers (MYH11) revealed that the NVTs and angiogenic sprouting tips recruited excessive PDGFRβ+ α-SMA+ MYH11- pericytes in OIR mice. Second, endothelial-specific Pdgf-b deletions were induced by the Cre-lox system, showing that endothelial PDGF-B was required for pericyte coverage and also promoted NVT formation in ischemic retinopathy. NCK1/2, which were SH2/3 adapter proteins, bound to phosphorylated Tyr-751 and Tyr-1009 in the activated PDGFR-β and further promoted fibroblast migration. Third, the NCK1/2 expression was reduced by NCK1/2 siRNA and Cre-lox system. NCK1/2 were required for PDGF-B-induced pericyte migration and neovascularization in OIR. In conclusion: (1) NVTs and newly sprouting tips are covered with abnormal α-SMA-expressing pericytes in OIR. (2) NCK1/2 signaling downstream of PDGFRβ promotes PDGF-B-induced pericyte migration.  

References:

  1. Eilken HM, et al. Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. 2017; 8: 1574.
  2. Edqvist PD, et al. Platelet-derived growth factor over-expression in retinal progenitors results in abnormal retinal vessel formation. 2012; Volume 7: Issue 8: e42488.