UCLA

Hemodynamic forces contribute to mechanotransduction and metabolomic pathways underlying microvascular development, remodeling, and atherogenesis. In micro-scale and developmental stages, microvascular adaptation, and remodeling in response to injury is modulated by spatiotemporal variations in wall shear stress (WSS); however, the underlying mechanisms and interplay leading to adaptation of microcirculation and remodeling at embryonic stage remain elusive. The understanding of the interplay between low Reynolds number (stokes flow) hemodynamic variations and microvascular adaptation provides translational implications in microvascular injury and repair for human diseases with associated vascular complications, such as diabetes and peripheral artery disease. In macro-scale and adult stage, disturbed flow and low WSS promote atherosclerosis which is mitigated as a result of exercise by changing the local hemodynamics and activating metabolomic transducers underlying vascular protection in the disturbed flow-prone vasculature. We used embryonic zebrafish tail as a microcirculation model and mouse aorta as a atherosclerosis model to investigate the role of flow-mediated microvascular remodeling and atherosclerosis development at different scales. In micro-scale, using computational fluid dynamics, we elucidated the interplay between WSS and vascular remodeling in zebrafish model of tail amputation and regeneration. The transgenic Tg (fli1:eGFP; Gata1:ds-red) zebrafish line was used to track the 3-D fluorescently-labeled vascular endothelium for post-image segmentation and reconstruction of fluid domain. Micro-particle image velocimetry was used to validate the blood flow. Following amputation to the dorsal aorta (DA) and posterior cardinal vein (PCV), vasoconstriction developed in the dorsal longitudinal anastomotic vessel (DLAV) along with increased WSS in the proximal segmental vessels (SV) from amputation. Angiogenesis ensued at the tips of the amputated DLAV and PCV where WSS was minimal. At 2 days post amputation (dpa), vasodilation occurred in a pair of SVs proximal to amputation, followed by increased blood flow and WSS, whereas in the SVs distal to amputation, WSS normalized to the baseline. At 3 dpa, the increase in blood flow in the arterial SV proximal to amputation promoted anastomosis with DLAV to form a loop with PCV. Thus, our in-silico modeling revealed the interplay between WSS and micro-vascular adaptation to changes in WSS and blood flow to restore micro-circulation following tail amputation. In macro-scale, we simulated exercise-augmented pulsatile shear stress (PSS) to mitigate flow recirculation in the lesser curvature of the aortic arch. Ultrasound-based 4-D+time moving boundary computational fluid dynamics analysis was performed on mouse aorta to simulate blood flow over several cardiac cycles. Exercise modulated the time-averaged shear stress (TAWSS) and oscillatory shear index (OSI), and upregulated SCD1 and attenuated well-known VCAM1 expression in the disturbed flow-prone aortic arch in Ldlr-/- mice on high-fat diet but not in Ldlr-/-Scd1EC-/- mice. When human aortic endothelial cells (HAECs) were subjected to PSS (τ_ave = 50 dyne�cm−2, ∂τ/∂t = 71 dyne�cm−2�s−1, 1 Hz), untargeted metabolomic analysis revealed that Stearoyl-CoA Desaturase (SCD1) in the endoplasmic reticulum (ER) catalyzed the fatty acid metabolite, oleic acid (OA), to mitigate inflammatory mediators. Following 24 hours of exercise, wild-type C57BL/6J mice developed elevated SCD1-catalyzed lipid metabolites in the plasma, including OA and palmitoleic acid (PA). Exercise over a 2-week period increased endothelial SCD1 in the ER. SCD1 overexpression via recombinant adenovirus also mitigated ER stress. Single cell transcriptomic analysis of the mouse aorta revealed interconnection of Scd1 with mechanosensitive genes, namely Irs2, Acox1 and Adipor2 that modulate lipid metabolic pathways. We found inverse relation between Scd1 and Vcam1 gene expression indicating the atheroprotective metabolites generated through Scd1 pathway. Taken together, exercise modulates PSS (TAWSS and OSI) to activate SCD1 as a metabolomic transducer to ameliorate inflammation in the disturbed flow-prone vasculature.