Extracellular HCO3- is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase Î 3

Abstract

We investigate sensing and signaling mechanisms for H+, HCO3- and CO2 in basilar arteries using out-of-equilibrium solutions. Selectively varying pH o, [HCO3-] o, or pCO2, we find: (a) lowering pH o attenuates vasoconstriction and vascular smooth muscle cell (VSMC) Ca2+-responses whereas raising pH o augments vasoconstriction independently of VSMC [Ca2+] i, (b) lowering [HCO3-] o increases arterial agonist-sensitivity of tone development without affecting VSMC [Ca2+] i but c) no evidence that CO2 has direct net vasomotor effects. Receptor protein tyrosine phosphatase (RPTP)γ is transcribed in endothelial cells, and direct vasomotor effects of HCO3 o- are absent in arteries from RPTPγ-knockout mice. At pH o 7.4, selective changes in [HCO3-] o or pCO2 have little effect on pH i. At pH o 7.1, decreased [HCO3-] o or increased pCO2 causes intracellular acidification, which attenuates vasoconstriction. Under equilibrated conditions, anti-contractile effects of CO2/HCO3-are endothelium-dependent and absent in arteries from RPTPγ-knockout mice. With CO2/HCO3- present, contractile responses to agonist-stimulation are potentiated in arteries from RPTPγ-knockout compared to wild-type mice, and this difference is larger for respiratory than metabolic acidosis. In conclusion, decreased pH o and pH i inhibit vasoconstriction, whereas decreased [HCO3-] o promotes vasoconstriction through RPTPγ-dependent changes in VSMC Ca2+-sensitivity. HCO3 o- serves dual roles, providing substrate for pH i-regulating membrane transporters and modulating arterial responses to acid-base disturbances.