Dataset Information

Sex-Specific Response to Combinations of Shear Stress and Substrate Stiffness by Endothelial Cells In Vitro.

ABSTRACT: By using a full factorial design of experiment, the combinatorial effects of biological sex, shear stress, and substrate stiffness on human umbilical vein endothelial cell (HUVEC) spreading and Yes-associated protein 1 (YAP1) activity are able to be efficiently evaluated. Within the range of shear stress (0.5-1.5 Pa) and substrate stiffness (10-100 kPa), male HUVECs are smaller than female HUVECs. Only with sufficient mechanical stimulation do they spread to a similar size. More importantly, YAP1 nuclear localization in female HUVECs is invariant to mechanical stimulation within the range of tested conditions whereas for male HUVECs it increases nonlinearly with increasing shear stress and substrate stiffness. The sex-specific response of HUVECs to combinations of shear stress and substrate stiffness reinforces the need to include sex as a biological variable and multiple mechanical stimuli in experiments, informs the design of precision biomaterials, and offers insight for understanding cardiovascular disease sexual dimorphisms. Moreover, here it is illustrated that different complex mechanical microenvironments can lead to sex-specific phenotypes and sex invariant phenotypes in cultured endothelial cells.

SUBMITTER: James BD

PROVIDER: S-EPMC8458248 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Sex-Specific Response to Combinations of Shear Stress and Substrate Stiffness by Endothelial Cells In Vitro.

James Bryan D BD Allen Josephine B JB

Advanced healthcare materials 20210617 18

By using a full factorial design of experiment, the combinatorial effects of biological sex, shear stress, and substrate stiffness on human umbilical vein endothelial cell (HUVEC) spreading and Yes-associated protein 1 (YAP1) activity are able to be efficiently evaluated. Within the range of shear stress (0.5-1.5 Pa) and substrate stiffness (10-100 kPa), male HUVECs are smaller than female HUVECs. Only with sufficient mechanical stimulation do they spread to a similar size. More importantly, YAP ...[more]

PMID: 34142471

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Project description:BackgroundIn blood vessels, the endothelium is a crucial signal transduction interface in control of vascular tone and blood pressure to ensure energy and oxygen supply according to the organs' needs. In response to vasoactive factors and to shear stress elicited by blood flow, the endothelium secretes vasodilating or vasocontracting autacoids, which adjust the contractile state of the smooth muscle. In endothelial sensing of shear stress, the osmo- and mechanosensitive Ca(2+)-permeable TRPV4 channel has been proposed to be candidate mechanosensor. Using TRPV4(-/-) mice, we now investigated whether the absence of endothelial TRPV4 alters shear-stress-induced arterial vasodilation.Methodology/principal findingsIn TRPV4(-/-) mice, loss of the TRPV4 protein was confirmed by Western blot, immunohistochemistry and by in situ-patch-clamp techniques in carotid artery endothelial cells (CAEC). Endothelium-dependent vasodilation was determined by pressure myography in carotid arteries (CA) from TRPV4(-/-) mice and wild-type littermates (WT). In WT CAEC, TRPV4 currents could be elicited by TRPV4 activators 4alpha-phorbol-12,13-didecanoate (4alphaPDD), arachidonic acid (AA), and by hypotonic cell swelling (HTS). In striking contrast, in TRPV4(-/-) mice, 4alphaPDD did not produce currents and currents elicited by AA and HTS were significantly reduced. 4alphaPDD caused a robust and endothelium-dependent vasodilation in WT mice, again conspicuously absent in TRPV4(-/-) mice. Shear stress-induced vasodilation could readily be evoked in WT, but was completely eliminated in TRPV4(-/-) mice. In addition, flow/reperfusion-induced vasodilation was significantly reduced in TRPV4(-/-) vs. WT mice. Vasodilation in response to acetylcholine, vasoconstriction in response to phenylephrine, and passive mechanical compliance did not differ between genotypes, greatly underscoring the specificity of the above trpv4-dependent phenotype for physiologically relevant shear stress.Conclusions/significanceGenetically encoded loss-of-function of trpv4 results in a loss of shear stress-induced vasodilation, a response pattern critically dependent on endothelial TRPV4 expression. Thus, Ca(2+)-influx through endothelial TRPV4 channels is a molecular mechanism contributing significantly to endothelial mechanotransduction.

Dataset Information

Sex-Specific Response to Combinations of Shear Stress and Substrate Stiffness by Endothelial Cells In Vitro.

Publications

Sex-Specific Response to Combinations of Shear Stress and Substrate Stiffness by Endothelial Cells In Vitro.

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