Peripheral ischemia is associated with higher degree of endothelial dysfunction and a worse prognosis after percutaneous coronary interventions (PCI). However, the role of peripheral ischemia on vascular remodeling in remote districts remains poorly understood. Here we show that the presence of hindlimb ischemia significantly enhances neointima formation and impairs endothelial recovery in balloon-injured carotid arteries. Endothelial-derived microRNAs are involved in the modulation of these processes. Indeed, endothelial miR-16 is remarkably upregulated after vascular injury in the presences of hindlimb ischemia and exerts a negative effect on endothelial repair through the inhibition of RhoGDIα and nitric oxide (NO) production. We showed that the repression of RhoGDIα by means of miR-16 induces RhoA, with consequent reduction of NO bioavailability. Thus, hindlimb ischemia affects negative carotid remodeling increasing neointima formation after injury, while systemic antagonizzation of miR-16 is able to prevent these negative effects.Peripheral Arterial Disease (PAD) affects approximately 20% of adults over the age of 50, exposing them to the negative impact of peripheral ischemia 1-3 . However, half of these subjects are asymptomatic. Hence, the actual impact of peripheral ischemia is largely under-estimated, leading to under-treatment and seriously undermining prevention strategies 4,5 . Interestingly, in patients with multidistrectual atherosclerosis the presence of peripheral ischemia is associated to a further increase in mortality independently of classical cardiovascular risk factors 6,7 . In line with these observations, it was shown that limb ischemia might remotely influence atherosclerotic vascular remodeling in coronary and cerebral districts 8,9 . Indeed, the presence of limb ischemia is often associated to endothelial dysfunction 10 , and consequently to a more severe atherosclerosis of remote districts 11 . Interestingly, patients with PAD and peripheral ischemia undergoing percutaneous coronary intervention (PCI) have a significantly poorer prognosis suggesting a remote negative impact of peripheral ischemia on coronary artery disease 12,13 . This picture has not improved with the recent significant progresses in medical therapy and introduction of the latest generation of drug eluting stents (DES) 14 . Indeed, it is known that limb ischemia can negatively influence vascular remodeling in other districts, such as coronary and cerebral arteries [12][13][14][15] . MicroRNA (miRNAs), small noncoding RNAs, have emerged in the last decade as epigenetic regulators of essential biological processes [15][16][17] . In particular, they play a key role in the pathophysiology of atherosclerosis, including restenosis after PCI [18][19][20] , and could be used as circulating biomarkers [21][22][23][24] . Recent studies showed that miRNAs could modulate both vascular smooth muscle cells (VSMC) and the endothelium in response to vascular injury 25 . Moreover, miRNAs can mediate intercellular crosstalk, involv...
