The Mechanobiology of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

Abstract

Endothelial cells (ECs) lining the cardiovascular system are subjected to a highly dynamic microenvironment resulting from pulsatile pressure and circulating blood flow. Endothelial cells are remarkably sensitive to these forces, which are transduced to activate signaling pathways to maintain endothelial homeostasis and respond to changes in the environment. Aberrations in these biomechanical stresses, however, can trigger changes in endothelial cell phenotype and function. One process involved in this cellular plasticity is endothelial-to-mesenchymal transition (EndMT). As a result of EndMT, ECs lose cell-cell adhesion, alter their cytoskeletal organization, and gain increased migratory and invasive capabilities. EndMT has long been known to occur during cardiovascular development, but there is now a growing body of evidence also implicating it in many cardiovascular diseases (CVD), often associated with alterations in the cellular mechanical environment. In this review, we highlight the emerging role of shear stress, cyclic strain, matrix stiffness, and composition associated with EndMT in CVD. We first provide an overview of EndMT and context for how ECs sense, transduce, and respond to certain mechanical stimuli. We then describe the biomechanical features of EndMT and the role of mechanically driven EndMT in CVD. Finally, we indicate areas of open investigation to further elucidate the complexity of EndMT in the cardiovascular system. Understanding the mechanistic underpinnings of the mechanobiology of EndMT in CVD can provide insight into new opportunities for identification of novel diagnostic markers and therapeutic interventions.

New insights into the pathogenesis of cardiac papillary fibroelastomas

“…Transforming growth factor beta TGFβ, is the most extensively studied mediator causing endothelial cells to undergo EndoMT. In in vitro experiments investigating the impact of inflammation on EndoMT, TGFβ is used alone as stimuli or in combination with tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) [46,47]. A few reports have shown that endothelial-to-mesenchymal transition is induced by mechanical forces (activators) such as flow and shear stress, matrix composition and stiffness, stretch and cyclic strain [47,48].…”

“…In in vitro experiments investigating the impact of inflammation on EndoMT, TGFβ is used alone as stimuli or in combination with tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) [46,47]. A few reports have shown that endothelial-to-mesenchymal transition is induced by mechanical forces (activators) such as flow and shear stress, matrix composition and stiffness, stretch and cyclic strain [47,48]. Accordingly, endothelial cells' responses to EndoMT triggers are heterogeneous and are dependent on different factors for example mechanical activators of EndoMT cause mechanical hallmarks such as endothelial monolayer disruption and invasion into the extracellular matrix [47].…”

“…A few reports have shown that endothelial-to-mesenchymal transition is induced by mechanical forces (activators) such as flow and shear stress, matrix composition and stiffness, stretch and cyclic strain [47,48]. Accordingly, endothelial cells' responses to EndoMT triggers are heterogeneous and are dependent on different factors for example mechanical activators of EndoMT cause mechanical hallmarks such as endothelial monolayer disruption and invasion into the extracellular matrix [47]. In the experimental study by Dal-Bianco et al, mechanical stress imposed by papillary muscle tethering led to the increase in the valve area and its thickness.…”

Regulation of Endothelial Progenitor Cell Functions in Ischemic Heart Disease: New Therapeutic Targets for Cardiac Remodeling and Repair

“…In ischemic or inflammatory tissue microenvironments with elevated ROS levels, the expression of catalase, copper-zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD) and anti-apoptotic factor Bcl-2 in EPCs was increased, supporting the supposition that ECs are resistant to ROS-induced toxicity, thereby maintaining their viability and functional activity ( 26 ). In addition, recent studies have shown that the endothelial-mesenchymal transition (EndMT) is an important process in vascular endothelial injury and is closely related to plaque stability and endothelial microenvironment homeostasis in coronary atherosclerosis ( 108 ). The EndMT causes ECs to lose their endothelial characteristics and acquire a mesenchymal-like cell (SMC and fibroblast) phenotype ( 109 , 110 ).…”

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

“…In the normal physiological condition, this cell fate conversion is necessary to properly form the cardiac valves of the developing heart [ 33 ]. However, EndoMT recurs postnatally during the development of various cardiovascular diseases (CVDs), such as atherosclerosis, adult valve diseases, myocardial fibrosis, and pulmonary arterial hypertension (PAH) [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. In the EndoMT transitional process, endothelial cells progressively lose endothelial-specific markers and gain mesenchymal phenotypes [ 45 ].…”