Vascular mechanotransduction

Abstract

This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.

Keywords: endothelial cells; flow-induced vasodilation; shear stress; vascular myogenic response; vascular smooth muscle cells.

Graphical abstract

FIGURE 1.

Mechanical forces acting on the arterial wall. Modified from Ref. , with permission from the American Physiological Society.

FIGURE 2.

Estimated mean wall shear stress (τ_w, log scale) in different longitudinal segments of the vascular tree under resting condition using the formula 4vη/r, where v is the mean linear velocity, η is blood viscosity, and r is vessel radius. The abscissa scale for the microcirculation [arterioles, capillaries (Caps.), venules] is lengthened in comparison to the large vessels (arteries and veins). From Ref. , with permission from Academic Press.

FIGURE 3.

Schematic drawing of streamlined antiatherogenic flow (e.g., thoracic aorta) and disturbed atherogenic flow (aortic arch and branch points) in the arterial tree. The figure is based on work from Refs. , and adapted from Ref. , with permission from the authors.

FIGURE 4.

Flow chambers. A: monoculture flow chambers with various geometries for the creation of different flow patterns. B: coculture flow chamber with Transwell for the investigations of cell-cell interactions under different flow patterns. WSS, wall shear stress. See glossary for other abbreviations.

FIGURE 5.

Stretch chambers. A: vertical mobile stretch chambers against indenters. B: stretch chambers with vacuum pulling against loading posts. C: longitudinal mobile stretch chamber for uniaxial stretch. D: microfluid channel-based stretch devices.

FIGURE 6.

Hypothesized relative time course of events contributing to flow-induced dilation. V_m: initial hyperpolarization through Kir2 channels followed by secondary depolarization (dotted red line) due to the activation of a Ca²⁺-activated Cl⁻ channel. [Ca²⁺]: initial Ca²⁺ release from endoplasmic reticulum (ER) stores, followed by sustained Ca²⁺ entry through various Ca²⁺-permeable ion channels. These events occur in parallel with or are followed by enhanced endothelial nitric oxide synthase (eNOS) phosphorylation. All these mechanisms combine to increase arterial diameter through inhibition of myogenic tone. See glossary for other abbreviations.

FIGURE 7.

Relationships between transmural pressure, σ_θ, and VSMC orientation. Cross-sectional (A) and axial (B) views of a blood vessel. See glossary for abbreviations.

FIGURE 8.

Various representations of the vascular myogenic response. A: time course of arterial myogenic constriction to a step increase in internal pressure. B: plot of arterial diameter as a function of pressure showing progressive constriction in physiological saline (active) vs. dilation in calcium-free physiological saline (passive). C: myogenic tone (passive-active) curves in B plotted as a function of pressure.

FIGURE 9.

Commonly used mechanotransduction assays for ion channels. A: application of shear stress to a single cell. B: stretch of a cell by substrate deformation. C: deformation of local membrane by patch pipette suction while recording single-channel currents. D: focal indentation of cell with mechanical probe while recording whole-cell current. E: deformation of cell (in this case inner ear hair cell) using fluid jet from micropipette while recording whole-cell current. F: deformation of inner ear hair cell with blunt probe while recording whole-cell current. G: osmotic swelling of cell. H: deformation of cell seeded onto elastomeric pillars. I: deformation of channel incorporated into bilayer by injection of asymmetric lipids. J: pressurization of a single cell through a whole-cell recording pipette. K: stretch of a single cell using two patch pipettes while recording whole-cell current. L: stretch of a single cell on flexible substrate using two blunt pipettes while recording whole-cell current. M: recording of current from patch of an excised, inside-out cell membrane while moving it into a flow stream from a pipette. N: localized deformation of a cell membrane by twisting of a magnetic bead attached to the cell surface. Modified from Ref. , with permission from Neuron.

FIGURE 10.

Possible mechanisms for gating a mechanosensitive ion channel. A: changes in bilayer tension alone. B: tension applied to channel through ECM tether. C: tension applied to channel through CSK tether. D: tension on 1 or more tethers exposes an intracellular binding domain. See glossary for abbreviations. Modified from Refs. –, with permission from Developmental Cell, Pflügers Archiv, and Nature, respectively.

FIGURE 11.

Ion channels in ECs and VSMCs that could potentially account for, or contribute to, flow-induced dilation and pressure-induced depolarization/constriction, respectively. Shear stress-induced activation of cation and Cl⁻ channels in ECs can produce depolarization, but the EC response is normally dominated by the activation of K⁺ channels, leading to a net hyperpolarization. See glossary for abbreviations.

FIGURE 12.

Postulated sequence of TRP, Ano1, K⁺, and voltage-dependent Ca²⁺ channel (VDCC) channel activation in VSMCs following a pressure step. The calcium source for Ano1 is not yet defined, but it may be activated by IP₃R-mediated Ca²⁺ release along with TRPM4. SR, sarcoplasmic reticulum. See glossary for other abbreviations.

FIGURE 13.

Postulated sequence of TRP, Ano1, K⁺, and voltage-dependent Ca²⁺ channel (VDCC) channel activation in VSMCs following a pressure step. Em, membrane potential. See glossary for other abbreviations.

FIGURE 14.

Signaling pathways downstream from PLC, PLD, and PLA₂. Based on Ref. , with permission from the American Physiological Society. DHETE, dihydroxyeicosatetraenoic acid; HETE, hydroxyeicosatetraenoic acid; Pchol, phosphatidylcholine. See glossary for other abbreviations.

FIGURE 15.

Schematic drawing showing mechanosensing molecules in endothelial cells.

FIGURE 16.

Ca²⁺-independent regulation of MLCP and constriction through Rho-ROCK signaling and control of actin polymerization. See glossary for abbreviations.

FIGURE 17.

Regulation of actin polymerization in VSMCs by GPCR and integrin signaling at the focal adhesion. See glossary for abbreviations.

FIGURE 18.

Schematic drawing showing mechanotransduction pathways in endothelial cells. ESG, endothelial surface glycocalyx; CNN, cyclins; LBK, liver kinase B1 (also called LKB1). See glossary for other abbreviations.

FIGURE 19.

Three major signaling pathways for myogenic constriction: 1) Ca²⁺-dependent regulation of MLCK downstream from VGCC gating by mechanosensitive GPCRs and second messenger-gated ion channels. TRPM4 is shown here as a representative but not exclusive ion channel target downstream from G_q/11 GPCRs. 2) Ca²⁺-independent regulation of MLPC through RhoK-ROCK signaling. 3) Rho regulation of actin polymerization. See glossary for abbreviations.

FIGURE 20.

Components of the Ca²⁺ entry and release mechanisms regulated by shear stress in ECs. Shear stress-activated proteins are colored in red. See glossary for abbreviations.

FIGURE 21.

Modulation of flow patterns in vivo. A: a schematic drawing of the flow patterns in native arteries. B: vessel constriction with cuffs to generate high shear at the cuff-narrowed neck and flow disturbance at the outlet of the neck. C: total ligation of left carotid artery (LCA) to create the flow cessation and back flow. D: ligations of external carotid (ECA)/internal carotid (ICA)/ophthalmic (OA) arteries on LCA to create low and disturbed flows. RCA, right carotid artery; STA, superficial temporal artery.

FIGURE 22.

Shear flow regulation of vascular cell interactions. Shear stress modulates endothelial function through EC mechanosensing and mechanotransduction processes to regulate the epigenome, transcriptome, and phenotypes, as well as the interactions (indicated by colored arrows) between ECs and the neighboring cells. Such regulation leads to homeostasis in health and pathophysiological changes in disease. lncR, long noncoding RNA. See glossary for other abbreviations.