Abstract
It is well-established that long-term exposure of the vasculature to metabolic disturbances leads to abnormal vascular tone, while the physiological regulation of vascular tone upon acute metabolic challenge remains unknown. Here, we found that acute glucose challenge induced transient increases in blood pressure and vascular constriction in humans and mice. Ex vivo study in isolated thoracic aortas from mice showed that glucose-induced vascular constriction is dependent on glucose oxidation in vascular smooth muscle cells. Specifically, mitochondrial membrane potential (ΔΨm), an essential component in glucose oxidation, was increased along with glucose influx and positively regulated vascular smooth muscle tone. Mechanistically, mitochondrial hyperpolarization inhibited the activity of myosin light chain phosphatase (MLCP) in a Ca2+-independent manner through activation of Rho-associated kinase, leading to cell contraction. However, ΔΨm regulated smooth muscle tone independently of the small G protein RhoA, a major regulator of Rho-associated kinase signaling. Furthermore, myosin phosphatase target subunit 1 (MYPT1) was found to be a key molecule in mediating MLCP activity regulated by ΔΨm. ΔΨm positively phosphorylated MYPT1, and either knockdown or knockout of MYPT1 abolished the effects of glucose in stimulating smooth muscle contraction. In addition, smooth muscle-specific Mypt1 knockout mice displayed blunted response to glucose challenge in blood pressure and vascular constriction and impaired clearance rate of circulating metabolites. These results suggested that glucose influx stimulates vascular smooth muscle contraction via mitochondrial hyperpolarization-inactivated myosin phosphatase, which represents a novel mechanism underlying vascular constriction and circulating metabolite clearance.
Highlights
Blood pressure (BP), one of the most commonly measured clinical parameters and one of the most commonly used indicators for cardiovascular health, is determined mainly by the blood volume, cardiac output, and vascular resistance[1,2,3]
Glucose challenge induced vascular constriction in vivo To examine the effects of glucose influx on vascular tone, a total of 8 healthy adults were recruited
Long-term exposure of the vasculature to metabolic disturbances leaves a persistent imprint on vascular smooth muscle cells (VSMCs), which potentially underlies macrovascular complications in metabolic disorders
Summary
Blood pressure (BP), one of the most commonly measured clinical parameters and one of the most commonly used indicators for cardiovascular health, is determined mainly by the blood volume, cardiac output, and vascular resistance[1,2,3]. Among these factors, vascular resistance depends on a balance between contraction and relaxation of vascular smooth muscle cells (VSMCs)[4,5]. Recent studies have shown that vascular smooth muscle tone is regulated by metabolism[7,8,9,10]. Mitochondria were reported to be involved in regulating VSMC contraction, proliferation, migration, and secretion; and mitochondrial dysfunction contributes to vascular pathologies such as atherosclerosis, stenosis, and hypertension[10,13,14,15]
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