While vascular remodeling is a key determinant of vascular lumen in (patho)physiological situations, its mediators remain poorly understood. Recently, we showed that the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1 (PDI) is markedly upregulated during vascular repair to injury, while its externalized pool (peri/epicellular PDI=pecPDI) counteracts constrictive remodeling through effects involving extracellular matrix and cytoskeletal organization, hydrogen peroxide production and beta1-integrin modulation. Importantly, ongoing investigation in the course of our PD project shows that such vascular repair effect reflects a general PDI-mediated mechanoadaptive regulation, since pecPDI neutralization significantly blunts cytoskeletal remodeling after cyclic stretch in cultured vascular smooth muscle cells (VSMC) or laminar shear in endothelial cells. However, upstream mechanisms of pecPDI mechanobiological effects are unknown. Our results intriguingly show that conditioned medium from stretched VSMC induce actin remodeling in static VSMC in a pecPDI-dependent manner. Recent investigation (including key contributions from the foreign supervisor) disclosed that microRNAs can regulate mechano-adaptation, with potential paracrine effects in endothelium-VSMC cross-talk. Here, we investigate whether paracrine signaling via microRNAs released from endothelial cells subjected to disturbed flow patterns affect VSMC signaling via pecPDI. The Specific Aims of this BEPE scholarship involve: (1) To investigate if disturbed flow affects microRNAs with potential to affect genes involved with the thioredoxin superfamily or cytoskeletal dynamics; (2) To analyze if microRNA derived from endothelial cells exposed to disturbed shear patterns affect VSMC PDI expression, location or associated cytoskeletal remodeling; (3) To assess if microRNA effects detected in aim (2) affect in vivo vessel remodeling. This BEPE project can provide significant contributions to our ongoing PD project and may indicate relevant novel mechanisms involving mechanobiological determinants of vascular disease processes.
News published in Agência FAPESP Newsletter about the scholarship: