Cardiovascular system can be regarded as a mechanical system centered on the heart. Blood flow in the vascular system, hemodynamics factors within the vasculature contain wall shear stress, circumferential wall tensile stress and hydrostatic pressure. Mechanical forces play an important role in vasculature and circulation, such as rapid regulation of vascular wall elasticity, administration of vascular remodeling, and the formation of arteriosclerotic lesions. Stress stimulation within the physiological range enables cells in dynamic balance to maintain homeostasis of vascular morphology, structure and function. Inversely, abnormal stresses stimulation, such as low shear stress, disturbed shear stress and high tensile strain, can break this balance and lead to vascular remodeling. Traditionally, blood pressure defines as a hydrostatic pressure on vascular wall. As a vertical pressure, hydrostatic pressure can act on all components of the vessel. However, few studies have addressed vascular smooth muscle cell (VSMC) (the most abundant component of the artery) under hydrostatic pressure as well as challenges to their function and the pathogenesis contributions to cardiovascular diseases.
First, researchers constructed a high-hydrostatic-pressure cell-culture system to imitate constant hypertension and applied single cell RNA-sequencing for identification a novel cellular taxonomy of VSMCs under hydrostatic pressure. Under 100-mmHg (analogous to healthy human blood pressure) or 200-mmHg (analogous to hypertension) hydrostatic pressure for 48 h, six distinct VSMC clusters were defined according to differential gene expression and gene ontology enrichment analysis. Especially, two novel VSMC subsets were identified, named the inflammatory subset, with CXCL2, CXCL3 and CCL2 as markers, and the endothelial-function inhibitory subset, with AKR1C2, AKR1C3, SERPINF1 as markers. The inflammatory subset promoted CXCL2&3 and CCL2 chemokine expression and secretion, triggering monocyte migration; the endothelial-function inhibitory subset secreted SERPINF1 and accelerated prostaglandin F2α generation to inhibit angiogenesis. The expression of the two VSMC subsets was greatly increased in arterial media from patients with hypertension and experimental animal models of hypertension.
Collectively, this study identified high hydrostatic pressure directly driving VSMCs into two new subsets, promoting or exacerbating endothelial dysfunction thereby contributing to the pathogenesis of other cardiovascular diseases such as coronary artery disease, stroke, and cardiac ischemic damage. The findings also partly explain why strict BP control (SBP <120 mmHg) significantly reduced all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). In the future, researchers can investigate how high hydrostatic pressure drives the two novel subsets and clarify the molecular mechanisms, which may indicate a novel pathway for explaining the genesis of hypertension and a novel target for anti-hypertension drug design.
This work was supported by the National Key R&D Program of China (NO.2018YFC1312703), CAMS Innovation Fund for Medical Sciences (CIFMS, NO. 2016-12M1-006), National Natural Science Foundation of China (NO. 81630014, 81825002, 81800367, 81870318, 81670379), and Beijing Outstanding Young Scientist Program (NO. BJJWZYJH01201910023029).
Featured image: High throughput single-cell RNA-sequencing of distinct cell clusters and heterogeneity of HASMCs. A, t-distributed scholastic neighbor embedding (t-SNE) plots with HASMC clusters demarcated by colors demonstrating six distinct clusters for 7,397 cells. B, Locations within thet-SNE plot of 100 and 200 mmHg. C, t-SNE plots show six clusters distributed under 100- and 200- mmHg pressure. D, Sample distribution in different clusters. E, Proportions of cell types across the different conditions (100 or 200 mmHg). © Chen et al.
See the article:
Chen, Z., Zhang, H., Bai, Y., Cui, C., Li, S., Wang, W., Deng, Y., Gao, Q., Wang, L., Qi, W., et al. (2021). Single cell transcriptomic analysis identifies novel vascular smooth muscle subsets under high hydrostatic pressure. Sci China Life Sci 64, https://doi.org/10.1007/s11427-020-1852-x
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