Abstract
Background:
Pulmonary hypertension (PH) is a progressive vascular disease that severely compromises quality of life and survival. The pulmonary endothelium plays a pivotal role in vascular homeostasis through complex signalling networks involving ion channels that respond to ionic imbalance (e.g. Na+, K+, Ca2+) and mechanical stimuli (e.g. via Piezo, TRPC, TRPV channels). While large-conductance calcium-activated potassium channels (BK channels), in pulmonary artery smooth muscle cells promote vasorelaxation and attenuate PH, their role in endothelial function is poorly defined. This study investigates the contribution of endothelial BK channels to pulmonary vascular signaling and their potential as therapeutic targets in PH.
Methods:
Human lung tissue samples from patients with idiopathic pulmonary arterial hypertension (IPAH) and healthy donors were assessed for BK channel expression by qPCR, Western blot and immunofluorescence staining. BK channel activity in human pulmonary artery endothelial cells was evaluated through patch-clamp recordings. In vivo, BK knockout (BK KO) mice and hypoxia-exposed wild-type mice were used to study endothelial dysfunction and vascular remodeling. Cellular metabolism was analyzed using oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), mitochondrial membrane potential and ROS were assessed by live cell imaging while ex vivo vasoreactivity was assessed via wire myography.
Results:
Wild type mice exposed to hypoxia (7 and 28 days) exhibited increased right ventricular systolic pressure (RVSP) and endothelial dysfunction with reduced BK channel function. BK KO mice showed impaired acetylcholine-induced vasodilation of pulmonary arteries, a sign of endothelial dysfunction, similar to mice exposed to hypoxia. BK KO endothelial cells displayed increased mitochondrial respiration, mitochondrial membrane hyperpolarization and increased cellular ROS production. In human PAECs (hPAECs), functional BK channels were identified and in IPAH patients, they were significantly downregulated. Pharmacological BK inhibition in hPAECs resulted in impaired nitric oxide (NO) production and uncontrolled angiogenesis. Furthermore, BK channels colocalized with Piezo-1, and their absence impaired Piezo-1-mediated calcium influx, suggesting a pivotal role in endothelial calcium signaling.
Conclusions:
BK channels are integral to pulmonary endothelial signalling, controlling vasodilation, angiogenesis, calcium dynamics, metabolic and oxidative homeostasis. Their impairment causes endothelial dysfunction in PH, and their downregulation in IPAH highlights a novel pathologic mechanism. Restoration of BK channel function may offer a new therapeutic strategy to improve endothelial function and counteract pulmonary vascular remodelling.
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Supplementary Information:
The online version contains supplementary material available at 10.1186/s12964-025-02436-0.
Keywords:
BK channels; Endothelial dysfunction; Hyperpolarization; Piezo-1 channels; Pulmonary hypertension; ROS.