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This study sought to determine the potential role of microRNAs (mi RNAs) in the detrimental effects of cigarette smoke on angiogenesis and neovascularization. Using large-scale mi RNA profiling and qRT- PCR analyses, we identified let-7f as a pro-angiogenic mi RNA 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 mi RNA mimic could constitute a novel therapeutic strategy to improve ischaemia-induced neovascularization in pathological conditions. [ABSTRACT FROM AUTHOR]