Mechanosensing in vascular health and disease

Mechanotransduction, once a neglected backwater compared to the central gene-message-protein dogma, has come of age. There is now a broad understanding of how mechanical forces from gravity, motor proteins, osmotic forces, tissue stiffness and fluid flow shape embryonic development, physiology and chronic diseases including cancer, osteoporosis, developmental defects, and tissue fibrosis. But nowhere are the effects of mechanical forces more central than in cardiovascular development, physiology, and diseases.

The essential function of the cardiovascular system is mechanical: to pump blood to every tissue in the body. Blood under pressure from cardiac contraction exerts a perpendicular force on vessel walls that expands the vessels to exert both circumferential and axial stress on the walls. Blood flow exerts fluid shear stress, the frictional force from fluid moving over a surface, on the endothelial cells that line the vasculature. It should come as no surprise that evolution has devised clever mechanisms by which the circulatory system exploits these forces to optimize its morphogenesis and function. Indeed, cells sense and transform forces into information that guides their gene expression, movement, and other functions. Thus, forces must be converted into the biochemical signals that govern gene transcription, cytoskeletal organization, cell movement and shape, metabolism, and so on. How mechanotransduction is accomplished is a topic of major interest and excitement, in particular, how the first step is achieved, i.e. the sensing of a mechanical force (mechanosensing). Protein modifications upon force are often used as readouts to identify mechanotransduction pathways. New understanding of these processes is now beginning to filter into translational research in the form of both device and drug development.

In adult organisms, critical variables are kept within acceptable ranges by homeostatic mechanisms that in essence “measure” relevant forces and adjust parameters to maintain the correct values. If blood pressure is too low, that is sensed by receptors in artery walls and steps are taken to increase blood volume, cardiac output and peripheral resistance to restore the desired level. Similarly, endothelial cells read out fluid shear stress and adjust vessel diameters to maintain the desired values.

Failure of homeostatic mechanisms in the cardiovascular system results in atherosclerosis and vascular malformations, cardiac valve disease and heart failure. All of these diseases can be considered forms of aberrant tissue remodeling that involve either abnormal forces or abnormal responses to forces. Atherosclerosis arises at regions of arteries subject to disturbances in shear stress patterns (bifurcations and regions of curvature) and is strongly accelerated by hypertension. Shear stress also drives hereditary hemorrhagic telangiectasia (HHT) lesions, in which mutation of components of the BMP9/10-Smad1/5 signaling pathway results in misreading of shear stress magnitude and subsequent abnormal remodeling. The list goes on.

The papers within this Collection reflect the breadth and importance of mechanobiology in cardiovascular health and disease. The Collection takes us from an atomic-level analysis of integrin αIIbβ3, a key mechanotransducer in platelet activation [1]; to cellular mechanotransduction through a formin [2]; to an investigation of microtubules in cellular mechanosensing [3]; to the role of forces in endothelial regeneration [4], and venous valve disease via the PIEZO1 channel [5]; to the role of mitochondrial energy metabolism and signaling in cell responses to stretch [6]; to an analysis of artery remodeling in response to mechanical unloading of the rat hindlimb [7]; to the effects of exercise on islet cell survival in type 2 diabetes [8]. The Collection thus spans dimensional scales from angstroms to centimeters, from development to physiology to disease, from genetics to biochemistry to cell biology to animal physiology.

We thank the journal editors who pushed us to take on this effort, the authors who contributed their fine work, and to all the readers who we hope will benefit.

Declarations

Competing interests

The Authors declare no competing interests.