Nikki L. Jernigan

Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelial sodium channel family that are emerging as multifaceted regulators of cardiovascular function. ASICs expressed in baroreceptor, cardiac, and skeletal muscle afferents contribute to reflex control of blood pressure, cardiac function, and sympathetic outflow. In vascular smooth muscle and endothelial cells, ASICs integrate mechanical, metabolic, and humoral signals to regulate vascular tone. In the systemic circulation, ASIC2 contributes to pressure-dependent vasoconstriction of renal and cerebral arteries, supporting blood flow autoregulation and protection against organ injury. In contrast, ASIC1a promotes vasodilation, contributing to nitric oxide-dependent dilation in the cerebral arteries and to endothelium-dependent hyperpolarization and vasodilation in mesenteric arteries. In the pulmonary vascular smooth muscle cells, ASIC1a plays a central role in acute hypoxic- and receptor-mediated vasoconstriction, a role that becomes increasingly important in chronic hypoxia-induced pulmonary hypertension. Under these conditions, metabolic reprogramming drives extracellular acidification and enhances ASIC1a trafficking to the plasma membrane, promoting sustained depolarization, augmented store-operated calcium entry, and a hyperproliferative, apoptosis-resistant smooth muscle phenotype. ASIC1a additionally regulates mitochondrial homeostasis by modulating mitochondrial membrane potential, redox balance, and apoptotic susceptibility. Chronic hypoxia redistributes ASIC1a from mitochondria to the plasma membrane, leading to mitochondrial dysfunction and cell survival signaling, key features of pulmonary vascular disease. This review summarizes current understanding of ASIC function in the systemic and pulmonary vasculature and highlights non-proton-mediated signaling mechanisms, emerging mitochondria-specific mechanisms, sex-related differences, and therapeutic opportunities and challenges in targeting ASIC-dependent signaling pathways in vascular disease.

This study identifies mitochondrial acid-sensing ion channel 1a (mtASIC1a) as a novel regulator of mitochondrial homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Critically, mtASIC1a deficiency in PASMCs following in vivo chronic hypoxia or genetic deletion promotes mitochondrial membrane potential (ΔΨm) hyperpolarization, Ca ²⁺ and superoxide (O ₂ ⁻ ) accumulation, impaired mitophagy, and caspase inhibition. Restoring mtASIC1a by lentiviral transduction prevents ΔΨm hyperpolarization and restores caspase cleavage, highlighting its importance in mitochondrial signaling and hypoxic pulmonary hypertension pathophysiology.

Acid‐sensing ion channel 1a (ASIC1a) is a proton‐gated cation channel activated by extracellular acidosis, a condition often associated with ischaemia, inflammation and metabolic stress. Our laboratory has previously demonstrated that ASIC1a contributes to systemic endothelium‐dependent vasodilatation; however, the role of ASIC1a in blood pressure regulation remains unclear. The objective of this study was to investigate the role of ASIC1a in blood pressure regulation using a model of angiotensin II‐induced hypertension. We further determined the effects of age and sex, as these are non‐modifiable risk factors for hypertension. Radiotelemeters were implanted in 6‐ and 18‐month‐old male and female wild‐type ( Asic1a ^+/+ ) and ASIC1a knockout ( Asic1a ^−/− ) mice to continuously measure blood pressure and heart rate under baseline conditions and following angiotensin II. Blood gases, electrolytes, hormones and indices of end‐organ injury were also assessed. Deletion of ASIC1 did not significantly alter blood pressure in 6‐month‐old male or female mice. However, aged male Asic1a ^−/− mice develop hypertension, whereas female Asic1a ^−/− mice remain unaffected. This hypertension was associated with aldosterone excess, increased sympathetic activity, and evidence of aortic fibrosis, left ventricular hypertrophy and renal injury. Importantly, hyperaldosteronism occurred independently of the renin–angiotensin system and was associated with blunting of angiotensin II‐induced hypertension. Prior to the onset of hypertension, 6‐month‐old male Asic1a ^−/− mice exhibit elevated corticosterone, hypokalaemia, reduced urine osmolality, increased pulse pressure and cardiomyocyte hypertrophy. Together, these findings identify ASIC1a as a novel, sex‐specific regulator of cardiovascular function, suggesting that ASIC1a deficiency may be a potential driver of endocrine‐related hypertension. image Key points: Extracellular acidosis, which occurs during pathological conditions such as ischaemia, inflammation and metabolic stress, contributes to the pathogenesis of cardiometabolic disease. Acid‐sensing ion channels (ASICs) are key sensors of acidosis and important mediators of endothelium‐dependent vasodilatation; however, the role of ASIC1a in blood pressure regulation remains poorly understood. Here we report that ASIC1a deficiency causes hypertension in aged male mice that is driven by an excess of aldosterone and increased sympathetic activity, while female mice remain unaffected. Hyperaldosteronism occurs independently of angiotensin II but is associated with elevated corticosterone that precedes the development of hypertension. We further show that male, but not female, ASIC1a knockout mice have a reduced sensitivity to angiotensin II‐induced hypertension. These findings identify ASIC1a as a novel, sex‐specific regulator of cardiovascular function, suggesting that ASIC1a deficiency contributes to endocrine‐related hypertension.

Pulmonary hypertension (PH) is a progressive vascular disease driven by pulmonary arterial remodeling, characterized by cellular hyperproliferation, resistance to apoptosis, and phenotypic plasticity. Our laboratory has shown that the proton-gated cation channel, acid-sensing ion channel 1a (ASIC1a), is essential for the development of chronic hypoxia (CH)-induced PH in rodents. Importantly, ASIC1a activation occurs without changes in total ASIC1a levels but reflects a hypoxia-dependent redistribution to the plasma membrane in pulmonary arterial smooth muscle cells (PASMCs). In neurons, mitochondrial-localized ASIC1a (mtASIC1a) contributes to oxidative stress-induced mitochondrial membrane potential (Δψm) depolarization and apoptosis. Although mtASIC1a has not been described in vascular cells, its role in PASMCs may be relevant to mitochondrial dysfunction and apoptosis resistance in PH. We hypothesize that mtASIC1a is a crucial regulator of PASMC mitochondrial homeostasis, and its loss following CH promotes mitochondrial dysfunction and apoptosis resistance. Consistent with this, mtASIC1a localization was decreased in PASMCs and intrapulmonary arteries from CH rats compared to controls. Functionally, PASMCs from CH rats or Asic1a knockout mice exhibited Δψm hyperpolarization, elevated mitochondrial Ca ²⁺ ; and superoxide, impaired mitophagy, and reduced cleaved caspase-3. Transmission electron microscopy revealed mitochondrial morphological changes, including increased size and circularity, decreased aspect ratio, and reduced mitochondrial number per cell, while fusion/fission proteins remained largely unchanged. Lentiviral restoration of mtASIC1a prevented Δψm hyperpolarization and restored caspase-3 cleavage. These findings identify mtASIC1a as a novel regulator of mitochondrial function in PASMCs, where its loss following CH promotes Δψm hyperpolarization, impaired mitophagy, and resistance to apoptosis.

Background: Acid-sensing ion channel 1a (ASIC1a) is an H ⁺ -gated cation channel that responds to extracellular acidosis in both normal and pathological states, including ischemia, inflammation, and metabolic disturbances. While ASIC1a regulates vascular reactivity, its role in blood pressure regulation remains unclear, particularly concerning sex, aging, and disease. This study aims to investigate whether ASIC1a: 1) contributes to cardiovascular function in a sex-dependent manner; 2) plays a dynamic role in cardiovascular homeostasis with aging; and 3) modulates the development of angiotensin II-induced systemic hypertension. Methods: Radiotelemeters were implanted in 6- and 18-month-old male and female wild-type ( Asic1a ^+/+ ) and ASIC1a knockout ( Asic1a ^-/- ) mice to monitor mean arterial blood pressure and heart rate under baseline conditions and in response to angiotensin II. Blood gases, electrolytes, hormones, and end-organ injury were also assessed. Results: Aged male Asic1a ^-/- mice develop hypertension driven by aldosterone excess and sympathetic overactivity, which is accompanied by cardiac hypertrophy, aortic fibrosis, and glomerular hypertrophy. Female Asic1a ^-/- mice remain unaffected. In male Asic1a ^-/- mice, hyperaldosteronism occurs independent of the renin-angiotensin system and mitigates angiotensin II-induced hypertension. Furthermore, 6-month-old male Asic1a ^-/- mice exhibit elevated corticosterone, hypokalemia, reduced urine osmolality, increased pulse pressure, and cardiomyocyte hypertrophy that precedes hypertension. Conclusions: These findings establish ASIC1a as a novel, sex-specific regulator of cardiovascular function, linking early corticosterone excess in male mice to hyperaldosteronism and implicating ASIC1a deficiency as a potential driver of endocrine-related hypertension. GRAPHICAL

In pulmonary hypertension, a metabolic shift to aerobic glycolysis drives a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells. We demonstrate that this enhanced glycolysis induces extracellular acidosis and activates the proton-gated ion channel, acid-sensing ion channel 1a (ASIC1a). Although multiple H⁺ transport/secretion mechanisms are upregulated in PHTN and likely contribute to extracellular acidosis, inhibiting glycolysis with 2-deoxy-d-glucose or syrosingopine effectively prevents extracellular acidification and ASIC1a activation, revealing a promising therapeutic avenue.

Pulmonary hypertension (PH) resulting from chronic hypoxia (CH) occurs in patients with chronic obstructive pulmonary diseases, sleep apnea, and restrictive lung diseases, as well as in residents at high altitude. Previous studies from our group and others demonstrate a detrimental role of reactive oxygen species (ROS) in the pathogenesis of CH-induced PH, although the subcellular sources of ROS are not fully understood. We hypothesized that mitochondria-derived ROS (mtROS) contribute to enhanced vasoconstrictor reactivity and PH following CH. To test the hypothesis, we exposed rats to 4 weeks of hypobaric hypoxia (P_B ≈ 380 mmHg), with control rats housed in ambient air (P_B ≈ 630 mmHg). Chronic oral administration of the mitochondria-targeted antioxidant MitoQ attenuated CH-induced decreases in pulmonary artery (PA) acceleration time, increases in right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary arterial remodeling. In addition, endothelium-intact PAs from CH rats exhibited a significantly greater basal tone compared to those from control animals, as was eliminated via MitoQ. CH also augmented the basal tone in endothelium-disrupted PAs, a response associated with increased mtROS production in primary PA smooth muscle cells (PASMCs) from CH rats. However, we further uncovered an effect of NO synthase inhibition with Nω–nitro-L-arginine (L-NNA) to unmask a potent endothelial vasoconstrictor influence that accentuates mtROS-dependent vasoconstriction following CH. This basal tone augmentation in the presence of L-NNA disappeared following combined endothelin A and B receptor blockade with BQ123 and BQ788. The effects of using CH to augment vasoconstriction and PASMC mtROS production in exogenous endothelin 1 (ET-1) were similarly prevented by MitoQ. We conclude that mtROS participate in the development of CH-induced PH. Furthermore, mtROS signaling in PASMCs is centrally involved in enhanced pulmonary arterial constriction following CH, a response potentiated by endogenous ET-1.

Acid-sensing ion channel 1a (ASIC1a) belongs to a novel family of proton-gated cation channels that are permeable to both Na⁺ and Ca²⁺. ASIC1a is expressed in vascular smooth muscle and endothelial cells in a variety of vascular beds, yet little is known regarding the potential impact of ASIC1a to regulate local vascular reactivity. Our previous studies in rat mesenteric arteries suggest ASIC1a does not contribute to agonist-induced vasoconstriction but may mediate a vasodilatory response. The objective of the current study is to determine the role of ASIC1a in systemic vasodilatory responses by testing the hypothesis that the activation of endothelial ASIC1a mediates vasodilation of mesenteric resistance arteries through an endothelium-dependent hyperpolarization (EDH)-related pathway. The selective ASIC1a antagonist psalmotoxin 1 (PcTX1) largely attenuated the sustained vasodilatory response to acetylcholine (ACh) in isolated, pressurized mesenteric resistance arteries and ACh-mediated Ca²⁺ influx in freshly isolated mesenteric endothelial tubes. Similarly, basal tone was enhanced and ACh-induced vasodilation blunted in mesenteric arteries from Asic1a knockout mice. ASIC1a colocalizes with intermediate- and small-conductance Ca²⁺-activated K⁺ channels (IK_Ca and SK_Ca, respectively), and the IK_Ca/SK_Ca-sensitive component of the ACh-mediated vasodilation was blocked by ASIC1a inhibition. To determine the role of ASIC1a to activate IK_Ca/SK_Ca channels, we measured whole-cell K⁺ currents using the perforated-patch clamp technique in freshly isolated mesenteric endothelial cells. Inhibition of ASIC1a prevented ACh-induced activation of IK_Ca/SK_Ca channels. The ASIC1 agonist, α/β-MitTx, activated IK_Ca/SK_Ca channels and induced an IK_Ca/SK_Ca-dependent vasodilation. Together, the present study demonstrates that ASIC1a couples to IK_Ca/SK_Ca channels in mesenteric resistance arteries to mediate endothelium-dependent vasodilation.

Hypoxia is the reduction of alveolar partial pressure of oxygen (P_AO₂). Military members and people who practice recreational activities from moderate to high altitudes are at risk for hypoxic exposure. Hypoxemia's signs and symptoms vary from asymptomatic to severe responses, such as excessive hypoxic ventilatory responses and residual neurobehavioral impairment. Therefore, it is essential to identify hypoxia-induced biomarkers to indicate people with exposure to hypoxia. Advances have been made in understanding physiologic responses to hypoxia, including elevations in circulating levels of endothelin 1 (ET-1) and micro RNA 21 (miR-21) and reduction in circulating levels of hydrogen sulfide (H₂S). Although the levels of these factors change upon exposure to hypoxia, it is unclear if these changes are sustained upon return to normoxia. We hypothesize that hypoxia-induced ET-1 and miR-21 remain elevated, while hypoxia-reduction in H₂S sustains after returning to normoxic conditions. To test this hypothesis, we exposed male rats to 6 hours of 12% O₂ and measured circulating levels of ET-1 and miR-21, pre, during, and post hypoxia. We found that ET-1 plasma levels increased in response to hypoxia but returned to normal levels within 30 minutes following the restoration of normoxia. miR-21 plasma levels and transdermal H₂S emissions decreased in response to hypoxia, remaining decreased upon return to normoxia, thus following the biomarker criteria. Therefore, this study supports a unique role for plasma miR21 and transdermal H₂S as hypoxia biomarkers that could be used to identify individuals after exposure to hypoxia.