Local acid–base disturbances arise physiologically during increased metabolic activity, such as intense exercise or heightened neuronal firing. In pathological conditions, including ischemia and solid tumours, acidic metabolites accumulate when blood flow fails to meet metabolic demand. We have uncovered novel mechanisms through which acid–base changes regulate cardiovascular function and influence susceptibility to ischemic injury.

Extracellular acid–base disturbances contribute to the metabolic regulation of cardiovascular function, but the underlying sensors and signalling pathways have remained elusive. Using out-of-equilibrium CO₂/HCO₃^– solutions, generated by rapidly mixing precursors with different CO₂, HCO₃^–, and pH compositions, we can independently control extracellular pH, HCO₃^–, and CO₂. Selective reductions in extracellular HCO₃^– at constant pH 7.4 and 5% CO₂ enhance cerebral artery contractions through a mechanism requiring receptor protein tyrosine phosphatase (RPTP)γ. Our findings reveal that RPTPγ, a transmembrane protein with homology to carbonic anhydrases, promotes vasodilation by augmenting endothelial Ca²⁺ signalling, endothelium-dependent hyperpolarization, and nitric oxide synthesis.

Cellular HCO₃^– uptake also contributes to intracellular pH regulation. In the vascular wall and cardiac atria, HCO₃^– uptake is mediated by the electroneutral Na⁺,HCO₃^–-cotransporter NBCn1 (SLC4A7). NBCn1 supports endothelial function by promoting nitric oxide synthesis. Loss of NBCn1 causes arterial hypertension and secondary cardiac hypertrophy, underscoring the importance of HCO₃^– transport in cardiovascular homeostasis.

Genetic analyses of UK Biobank data identify PTPRG, the gene encoding RPTPγ, as a risk locus for ischemic disease in the heart and brain. Consistent with this association, RPTPγ-deficient mice show increased vulnerability to hypoxia, greater susceptibility to stroke, and exacerbated cardiac ischemic injury following reduced organ perfusion. These mice also exhibit diminished exercise capacity during both forced and voluntary running. RNA sequencing reveals attenuated exercise-induced transcriptional adaptation and a markedly enhanced inflammatory response to ischemia.

In this presentation, I will discuss the multifaceted roles of HCO₃^– in cardiovascular physiology: as a substrate for membrane transporters that regulate intracellular pH, as a signal that modulates smooth-muscle and endothelial function, and as a determinant of vascular responses to acid–base disturbances arising from increased metabolic demand.