Abstract
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.
Highlights
The blood flow was evaluated by laser doppler imaging at day 0, 7, 14 and 28 after hindlimb ischemia to assess the efficiency of the ligation procedure and the development of collateral blood flow (Supplemental Fig. 2A)
No substantial difference in the expression levels of the specific vascular smooth muscle cells (VSMC) markers SM22 and Calponin (Supplemental Fig. 2B) or proliferation (Fig. 1a and Supplemental Fig. 2C) in injured arteries was found between BI and femoral artery ligation (FL)-BI groups
The major findings of the present study are that: i) hindlimb ischemia remotely enhances neointimal hyperplasia and impairs endothelial recovery of the carotid artery after balloon injury; ii) miR-16 mediates, at least in part, the adverse impact of hindlimb ischemia on remote vascular remodeling at the carotid artery; iii) inhibition of miR-16, using a specific antagomir, is able to reduce the negative impact exerted by hindlimb ischemia
Summary
Despite it has been described that peripheral ischemia can negatively influence remote vascular remodeling[12,13,14,15], at the present time it is currently unclear how peripheral ischemia may influence vascular response to injury in a remote district, and whether miRNAs are involved in these phenomena. In this context, aim of the present study was to assess the remote effects of hindlimb ischemia on neointimal proliferation and endothelial recovery after balloon injury of the carotid artery, to investigate the molecular mechanisms underlying these phenomena
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