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Extracellular HCO3- is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase ?.

ABSTRACT: We investigate sensing and signaling mechanisms for H(+), [Formula: see text] and CO2 in basilar arteries using out-of-equilibrium solutions. Selectively varying pHo, [[Formula: see text]]o, or pCO2, we find: (a) lowering pHo attenuates vasoconstriction and vascular smooth muscle cell (VSMC) Ca(2+)-responses whereas raising pHo augments vasoconstriction independently of VSMC [Ca(2+)]i, (b) lowering [[Formula: see text]]o increases arterial agonist-sensitivity of tone development without affecting VSMC [Ca(2+)]i but c) no evidence that CO2 has direct net vasomotor effects. Receptor protein tyrosine phosphatase (RPTP)? is transcribed in endothelial cells, and direct vasomotor effects of [Formula: see text] are absent in arteries from RPTP?-knockout mice. At pHo 7.4, selective changes in [[Formula: see text]]o or pCO2 have little effect on pHi At pHo 7.1, decreased [[Formula: see text]]o or increased pCO2 causes intracellular acidification, which attenuates vasoconstriction. Under equilibrated conditions, anti-contractile effects of CO2/[Formula: see text] are endothelium-dependent and absent in arteries from RPTP?-knockout mice. With CO2/[Formula: see text] present, contractile responses to agonist-stimulation are potentiated in arteries from RPTP?-knockout compared to wild-type mice, and this difference is larger for respiratory than metabolic acidosis. In conclusion, decreased pHo and pHi inhibit vasoconstriction, whereas decreased [[Formula: see text]]o promotes vasoconstriction through RPTP?-dependent changes in VSMC Ca(2+)-sensitivity. [Formula: see text] serves dual roles, providing substrate for pHi-regulating membrane transporters and modulating arterial responses to acid-base disturbances.

SUBMITTER: Boedtkjer E

PROVIDER: S-EPMC4853837 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Extracellular HCO3- is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ.

Boedtkjer Ebbe E Hansen Kristoffer B KB Boedtkjer Donna M B DMB Aalkjaer Christian C Boron Walter F WF

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20151019 5

We investigate sensing and signaling mechanisms for H(+), [Formula: see text] and CO2 in basilar arteries using out-of-equilibrium solutions. Selectively varying pHo, [[Formula: see text]]o, or pCO2, we find: (a) lowering pHo attenuates vasoconstriction and vascular smooth muscle cell (VSMC) Ca(2+)-responses whereas raising pHo augments vasoconstriction independently of VSMC [Ca(2+)]i, (b) lowering [[Formula: see text]]o increases arterial agonist-sensitivity of tone development without affectin ...[more]

PMID: 26661205

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Project description:The human brain requires adequate cerebral blood flow to meet the high demand for nutrients and to clear waste products. With age, there is a chronic reduction in cerebral blood flow in small resistance arteries that can eventually limit proper brain function. The endothelin system is a key mediator in the regulation of cerebral blood flow, but the contributions of its constituent receptors in the endothelial and vascular smooth muscle layers of cerebral arteries have not been well defined in the context of aging. We isolated posterior cerebral arteries from young and aged Fischer 344 rats, as well as ETB receptor knock-out rats and mounted the vessels in plexiglass pressure myograph chambers to measure myogenic tone in response to increasing pressure and targeted pharmacological treatments. We used an ETA receptor antagonist (BQ-123), an ETB receptor antagonist (BQ-788), endothelin-1, an endothelin-1 synthesis inhibitor (phosphoramidon), and vessel denudation to dissect the roles of each receptor in aging vasculature. Aged rats exhibited a higher myogenic tone than young rats, and the tone was sensitive to the ETA antagonist, BQ-123, but insensitive to the ETB antagonist, BQ-788. By contrast, the tone in the vessels from young rats was raised by BQ-788 but unaffected by BQ-123. When the endothelial layer that is normally enriched with ETB1 receptors was removed from young vessels, myogenic tone increased. However, denudation of the endothelial layer did not influence vessels from aged animals. This indicated that endothelial ETB1 receptors were not functional in the vessels from aged rats. There was also an increase in ETA receptor expression with age, whereas ETB receptor expression remained constant between young and aged animals. These results demonstrate that in young vessels, ETB1 receptors maintain a lower myogenic tone, but in aged vessels, a loss of ETB receptor activity allows ETA receptors in vascular smooth muscle cells to raise myogenic tone. Our findings have potentially important clinical implications for treatments to improve cerebral perfusion in older adults with diseases characterized by reduced cerebral blood flow.

Project description:Arterioles maintain blow flow by adjusting their diameter in response to changes in local blood pressure. In this process called the myogenic response, a vascular smooth muscle mechanosensor controls tone predominantly through altering the membrane potential. In general, myogenic responses occur slowly (minutes). In the heart and skeletal muscle, however, tone is activated rapidly (tens of seconds) and terminated by brief (100 ms) arterial constrictions. Previously, we identified extensive expression of TRPV1 in the smooth muscle of arterioles supplying skeletal muscle, heart and fat. Here we reveal a critical role for TRPV1 in the rapid myogenic tone of these tissues. TRPV1 antagonists dilated skeletal muscle arterioles in vitro and in vivo, increased coronary flow in isolated hearts, and transiently decreased blood pressure. All of these pharmacologic effects were abolished by genetic disruption of TRPV1. Stretch of isolated vascular smooth muscle cells or raised intravascular pressure in arteries triggered Ca2+ signalling and vasoconstriction. The majority of these stretch-responses were TRPV1-mediated, with the remaining tone being inhibited by the TRPM4 antagonist, 9-phenantrol. Notably, tone developed more quickly in arteries from wild-type compared with TRPV1-null mice. Furthermore, the immediate vasodilation following brief constriction of arterioles depended on TRPV1, consistent with a rapid deactivation of TRPV1. Pharmacologic experiments revealed that membrane stretch activates phospholipase C/protein kinase C signalling combined with heat to activate TRPV1, and in turn, L-type Ca2+ channels. These results suggest a critical role, for TRPV1 in the dynamic regulation of myogenic tone and blood flow in the heart and skeletal muscle. KEY POINTS: We explored the physiological role of TRPV1 in vascular smooth muscle. TRPV1 antagonists dilated skeletal muscle arterioles both ex vivo and in vivo, increased coronary perfusion and decreased systemic blood pressure. Stretch of arteriolar myocytes and increases in intraluminal pressure in arteries triggered rapid Ca2+ signalling and vasoconstriction respectively. Pharmacologic and/or genetic disruption of TRPV1 significantly inhibited the magnitude and rate of these responses. Furthermore, disrupting TRPV1 blunted the rapid vasodilation evoked by arterial constriction. Pharmacological experiments identified key roles for phospholipase C and protein kinase C, combined with temperature, in TRPV1-dependent arterial tone. These results show that TRPV1 in arteriolar myocytes dynamically regulates myogenic tone and blood flow in the heart and skeletal muscle.

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Extracellular HCO3- is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase ?.

Publications

Extracellular HCO3- is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ.

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