Therefore, if the sensor of increased flow could be identified there would be an advance in understanding how humans respond to exercise and achieve health benefits. Physical activity increases the rate of blood flow ( 11), so the benefits of exercise might originate at least partly in the detection of this increased flow. The endothelium consists of a monolayer of cells lining the inner surface of all blood vessels throughout the body: the cellular interface between blood and tissue and the only structure known to detect the rate of blood flow, something at which it is highly adept ( 14– 16). Exercise research has suggested that the site of the sensor might be the endothelium and that blood flow or other hemodynamic parameters are sensed ( 11– 13). It is reasonable to suppose that there must be a biological system containing a sensor or sensors to indicate to the body how much physical activity is occurring, but the sensor is obscure. The World Health Organization suggests that physical inactivity is the fourth leading cause of death worldwide.Īlthough many responses to exercise are known, how the benefits of exercise are initially triggered at a molecular level is mysterious. However, there are major challenges due to illness, injuries, and the intellectual and computational demands of modern societies that increase the prevalence of sedentary lifestyles. We know that if every human could maintain a suitable level of exercise and fitness, many disease problems would be less severe and quality of life would be better. Exercise is commonly encouraged, even prescribed, as therapy. Since the first epidemiological studies ( 3), research has continued to bestow on us a wealth of evidence that exercise protects against a host of ailments and life-threatening conditions that affect large numbers of people in 21st-century societies through heart attacks, strokes, diabetes, depression, dementia, cancer, osteoporosis, chronic kidney disease, and sexual dysfunction ( 4– 10). At least 2500 years ago it was first documented that exercise is good for health ( 1, 2). Lack of physical activity results in detraining, lower performance, and ultimately, incapacity. Physical fitness is important for survival. The data suggest an endothelial cell–pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability. In endothelial cells, Piezo1 was required for normal expression of endothelial NO synthase. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without an effect on Tsp1. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial cell apoptosis, with no effect on TSP1, a related important player in muscle physiology. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. Conditional endothelial cell–specific deletion of Piezo1 in adult mice depressed physical performance. Here we reveal an important role in the control of capillary density. Piezo1 forms mechanically activated nonselective cation channels that contribute to endothelial response to fluid flow.
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