Vascular Endothelial Cell Behavior in Complex Mechanical Microenvironments

Abstract

The vascular mechanical microenvironment consists of a mixture of spatially and temporally changing mechanical forces. This exposes vascular endothelial cells to both hemodynamic forces (fluid flow, cyclic stretching, lateral pressure) and vessel forces (basement membrane mechanical and topographical properties). The vascular mechanical microenvironment is "complex" because these forces are dynamic and interrelated. Endothelial cells sense these forces through mechanosensory structures and transduce them into functional responses via mechanotransduction pathways, culminating in behavior directly affecting vascular health. Recent in vitro studies have shown that endothelial cells respond in nuanced and unique ways to combinations of hemodynamic and vessel forces as compared to any single mechanical force. Understanding the interactive effects of the complex mechanical microenvironment on vascular endothelial behavior offers the opportunity to design future biomaterials and biomedical devices from the bottom-up by engineering for the cellular response. This review describes and defines (1) the blood vessel structure, (2) the complex mechanical microenvironment of the vascular endothelium, (3) the process in which vascular endothelial cells sense mechanical forces, and (4) the effect of mechanical forces on vascular endothelial cells with specific attention to recent works investigating the influence of combinations of mechanical forces. We conclude this review by providing our perspective on how the field can move forward to elucidate the effects of the complex mechanical microenvironment on vascular endothelial cell behavior.

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

“…Traditionally, the influence of fluid shear stress and associated traction forces and strains on endothelial cell (EC) physiology and function have been studied in reductionist models (e.g., parallel plate flow chambers, 2D substrates, transwell inserts). [ 7,8,37,38 ] These studies have provided significant insights into critical aspects of vascular morphogenesis, differentiation, barrier function, diffusional transport, and paracrine signaling mechanisms. In particular, these models are excellent for decoupling the roles of several interconnected flow parameters with complex associations on vascular processes.…”

“…In general, large blood vessels consist of three concentric layers: 1) tunica intima, 2) tunica media, and 3) tunica adventitia ( Figure ). [ 7 ] The tunica intima is the innermost lining consisting of an EC monolayer supported on a thin basement membrane (BM) (primarily composed of type IV collagen and laminin). Since it is in direct contact with blood flow, the EC lumen regulates the transport of nutrients and other soluble factors from the blood to the parenchymal tissue through a tightly‐regulated barrier.…”

“…Adapted with permission. [ 7 ] Copyright 2018, American Chemical Society. B) Schematic of the forces acting on blood vessels and the phase lag between wall shear stress (WSS) and circumferential strain (CS) characterized by the stress phase angle (SPA).…”

“…VEGF, PDGF, and surface receptor expression, e.g., Ang‐1, ‐2), and 4) inflammation (via induced expression of E‐selectin, intercellular adhesion molecule (ICAM)‐1, or vascular cell adhesion molecule (VCAM)‐1 in response to inflammatory molecules, (interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, interferon (IFN)‐γ, or reactive oxygen species (ROS)). [ 7,8 ]…”

“…[ 4 ] Past research has implicated several factors, which regulate vascular structure and function at the cellular and tissue level, including hemodynamic variations, traction forces at the endothelial substratum, extracellular matrix (ECM) characteristics, cell–cell, and cell–matrix interactions, and others. [ 5–11 ] Comprehensive mechanistic investigation of these processes is necessary to understand disease progression and ultimately develop therapeutic strategies to prevent and mitigate chronic and acute vascular pathologies.…”