Abstract
This study sought to determine the potential role of microRNAs (miRNAs) in the detrimental effects of cigarette smoke on angiogenesis and neovascularization. Using large‐scale miRNA profiling and qRT‐PCR analyses, we identified let‐7f as a pro‐angiogenic miRNA which expression is significantly reduced in HUVECs treated with cigarette smoke extracts (CSE), and in the ischemic muscles of mice that are exposed to cigarette smoke (MES). In a mouse model of hindlimb ischaemia, intramuscular injection of let‐7f mimic restored ischaemia‐induced neovascularization in MES. Doppler flow ratios and capillary density in ischemic muscles were significantly improved in MES treated with let‐7f mimic. Clinically, this was associated with reduced ambulatory impairment and hindlimb ischaemic damage. Treatment with let‐7f mimic could also rescue pro‐angiogenic cell (PAC) number and function (attachment, proliferation, migration) in MES. ALK5 (TGF‐βR1), an important modulator of angiogenesis, is a target of let‐7f. Here we show that ALK5 is increased in HUVECs exposed to CSE and in the ischaemic muscles of MES. This is associated with a downstream activation of the anti‐angiogenic factors SMAD2/3 and PAI‐1. Importantly, treatment with let‐7f mimic reduces the expression of ALK5, SMAD2/3 and PAI‐1 both in vitro and in vivo. Moreover, let‐7f overexpression or ALK5 inhibition can rescue angiogenesis in HUVECs exposed to CSE. Cigarette smoke exposure is associated with reduced expression of let‐7f and activation of the anti‐angiogenic TGF‐β/ALK5 pathway. Overexpression of let‐7f using a miRNA mimic could constitute a novel therapeutic strategy to improve ischaemia‐induced neovascularization in pathological conditions.
Highlights
IntroductionOne of the most important physiological responses to maintain tissue integrity is the ability to develop new blood vessels (neovascularization) [1]
After ischaemia, one of the most important physiological responses to maintain tissue integrity is the ability to develop new blood vessels [1]
We used Affimetrix microarray analyses to identify potential angiomiRs that could be impaired in Human umbilical vein endothelial cells (HUVECs) exposed to cigarette smoke extracts (CSE)
Summary
One of the most important physiological responses to maintain tissue integrity is the ability to develop new blood vessels (neovascularization) [1]. Neovascularization is a complex process that necessitates the activation, the proliferation and the migration of mature endothelial cells in order to extend the pre-existing vascular network (i.e. angiogenesis) [2]. PACs have been shown to reach sites of ischaemia where they promote neovascularization mainly through paracrine secretion of growth factors and cytokines [5]. Angiogenesis and neovascularization are dependent on important growth factors such as vascular endothelial growth factor (VEGF) [6], fibroblast growth factor (FGF) [7] and nitric oxide (NO) [8, 9]. Members of the transforming growth factor-b (TGF-b) superfamily have been shown to exert important functional effects in endothelial cells, and it has been proposed that these effects can vary depending on the context. Whereas ALK5 inhibits EC migration and proliferation, ALK1 promotes both processes after stimulation by TGF-b1 [11, 12]
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