p75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia

Abstract

The communication between vascular endothelial cells (ECs) and pericytes in the microvasculature is fundamental for vascular growth and homeostasis; however, these processes are disrupted by diabetes. Here we show that modulation of p75NTR expression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75NTR activates NF-κB to bind the miR-503 promoter and upregulate miR-503 expression in ECs. NF-κB further induces activation of Rho kinase and shedding of endothelial microparticles carrying miR-503, which transfer miR-503 from ECs to vascular pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduces expression of EFNB2 and VEGFA, resulting in impaired migration and proliferation. We confirm operation of the above mechanisms in mouse models of diabetes, in which EC-derived miR-503 reduces pericyte coverage of capillaries, increased permeability and impaired post-ischaemic angiogenesis in limb muscles. Collectively, our data demonstrate that miR-503 regulates pericyte–endothelial crosstalk in microvascular diabetic complications.

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction

“…One important feature of hAPCs consists of their ability to modulate angiogenesis via direct contacts with, and transfer of paracrine growth factors and microRNAs to endothelial cells 9, 16, 28. Therefore, we next investigated whether sAPCs share similar properties by testing their capacity to promote endothelial cell network formation in a Matrigel assay.…”

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

“…34 It was recently reported that ECs are able to release and transfer miR-503 to pericytes through microparticle trafficking. 35 This mechanism has important implications for vascular complications of diabetes mellitus. 35 It was shown that platelets are enriched with a large number of miRNAs, which are continuously exchanged between platelets, platelets-derived microparticles, and other cell populations.…”

“…35 This mechanism has important implications for vascular complications of diabetes mellitus. 35 It was shown that platelets are enriched with a large number of miRNAs, which are continuously exchanged between platelets, platelets-derived microparticles, and other cell populations. In fact, platelet and their shedding microparticles were proposed to provide horizontal transfer of biological information through iRNA trafficking.…”

“…19,21,23,25,28,29 In particular, several aspects of the vascular response to injury are modulated by miRNAs 19,30,31 that can also mediate cell-to-cell communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) within the vessel wall and with other cells' populations, such as monocytes, pericytes, or platelets. [32][33][34][35][36] In particular, besides their direct involvement in several aspects of thrombosis, atherosclerosis, and vascular remodeling, 37 platelets contain large amounts of miRNAs and largely [38][39][40] The aim of the present review is to summarize laboratory and clinical evidences on the role played by miRNAs in vascular biology, with special focus on their potential clinical impact.…”

Cell Therapy and Critical Limb Ischemia: Evidence and Window of Opportunity in Obesity

“…Typically, C57Bl6 mice are used over the age of 12 weeks, as younger animals recover so quickly and completely that angiogenic agents cannot be easily tested [27]. Majority of CLI preclinical data are generated using type 1 diabetic model induced by the toxin streptozotocin injection [46][47][48].…”