Fluid shear stress sensing in vascular homeostasis and remodeling: Towards the development of innovative pharmacological approaches to treat vascular dysfunction

Abstract

Blood circulation, facilitating gas exchange and nutrient transportation, is a quintessential feature of life in vertebrates. Any disruption to blood flow, may it be by blockade or traumatic rupture, irrevocably leads to tissue infarction or death. Therefore, it is not surprising that hemostasis and vascular adaptation measures have been evolutionarily selected to mitigate the adverse consequences of altered circulation. Blood vessels can be broadly categorized as arteries, veins, or capillaries, based on their structure, hemodynamics, and gas exchange. However, all of them share one property: they are lined with an epithelial sheet called the endothelium, which typically lies on a basement membrane. This endothelium is the primary interface between the flowing blood and the rest of the body, and it has highly specialized molecular mechanisms to detect and respond to changes in blood perfusion. The purpose of this commentary will be to highlight some of the recent developments in the research on blood flow sensing, vascular remodeling, and homeostasis and to discuss the development of innovative pharmaceutical approaches targeting mechanosensing mechanisms to prolong patient survival and improve quality of life. 1. Introduction: physiology of blood flow sensation and adaptation One of the earliest observations of vascular adaptation in response to changes in hemodynamics was made in the nineteenth century by Thoma and these were further investigated by Chapman and Murray in the chick yolk sac; adequate perfusion was found to determine which premature, non-perfused, and unspecified vessels undergo arterial specification and maturation, while under-perfused vessels remain closed and regress [1-3]. These earlier observations are striking: blood vessels are not merely biological pipes, they are dynamic structures shaped by blood flow itself. This dynamic adaptation is not restrained to the developmental stages of the vasculature, with a transient increase in arterial flow being associated with a transient dilation of the mature arteries under increased flow, through vasorelaxant release [4-8]. Furthermore, a sustained increase in flow, as observed in the muscular arteries of physically trained individuals [9,10] or in the uterine artery during pregnancy [11,12], triggers active remodeling of the concerned arteries by increasing their lumen diameter, improving tissue perfusion. Similarly, hypoperfusion of mature blood vessels, following stenosis for example, leads to the inward remodeling of under-perfused vessels. Interestingly, this inward remodeling could not be linked to an increased contraction of the mural cells as vasorelaxants could not relieve it [13]. This indicates a more profound, structural adaptation of the vessel in response to changes in flow. This was later confirmed after observing that mice lacking matrix metalloproteinases could not undergo successful inward remodeling in response to decreased flow due to the lack of remodeling of the collagen matrix [14,15]. These observations, in various animal m...

A Network Pharmacology-Based Study on Active Ingredients of Corydalis Rhizoma on Coronary Heart Disease

“…After KEGG enrichment analysis and removal of wide range of metabolic pathways, we concluded 5 top pathways with the highest enrichment scores, including uid shear stress and atherosclerosis, TNF signaling pathway, apoptosis, MAPK signaling pathway, PI3K-Akt signaling pathway. Sensing of uid shear stress and atherosclerosis is considered important in processes of vascular development and remodeling [59,60]. Studies demonstrated that TNF antagonists has a potent effect of anti-in ammatory and antioxidant [61,62].…”

Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

“…Disruption of normal cell-to-cell contacts in the vascular endothelium accompanies excessive shear force and leads to an inflammatory response characterized by monocyte adhesion (3,31). Having demonstrated that shear force activates Piezo1 which can disrupt AJs and form paracellular gaps in confluent monolayers we next evaluated the effects of Piezo1 on endothelial cell activation and adhesion protein expression, which are two of the early processes in atherosclerosis (41).…”

“…Blood flowing across endothelial cells within blood vessels generates shear stress. Under normal physiological conditions, a dynamic balance between mechanical shear stress and biological responses maintains endothelial integrity (1)(2)(3)(4)(5). Shear stress induces the release of endothelial vasodilatory factors such as nitric oxide, prostacyclin, and cytochrome P-450 metabolites of arachidonic acid that are required for underlying smooth muscle relaxation (6)(7)(8).…”

“…Endothelial Ca 2+ -mediated mechanosensing is required for normal flow-mediated dilation (4,5). Perturbation of endothelial shear stress that occurs with hypertension or excessive flow leads to vascular remodeling through the disruption of cytoskeletal proteins and vascular dysfunction involving the loss of endothelial integrity, increased endothelial cell stiffness, altered vasorelaxation properties, and leukocyte adhesion (2,3,(9)(10)(11)(12)(13).…”

“…Clinically, high venous pressure is a major cause of pulmonary edema and mortality in patients with congestive heart failure (10,11). Elevated vascular pressure can lead to endothelial barrier disruption and hyperpermeability due to loss of adherens junctions (AJs) between endothelial cells (3,11). It has recently been demonstrated that the mechanosensitive ion channel Piezo1 mediates pressure-induced disruption of AJs and endothelial barrier breakdown in pulmonary vessels (11,14).…”