Journal of Physiology-London最新文献

Cardiovascular diseases remain the leading cause of mortality worldwide, driven by complex, multiscale mechanisms that span molecular, cellular and organ-level dysfunction. Effective therapeutic strategies therefore require integrative approaches that link fundamental biology to translational applications. The 8^th UC Davis CardioVascular Symposium gathered experts in ion channel biophysics, Ca²⁺ signalling, arrhythmia mechanisms and cardiovascular physiology to discuss recent advances and define emerging priorities. This white paper synthesizes the key themes and consensus points that emerged, highlighting progress in two core domains: (1) advances in cardiovascular electrophysiology and arrhythmia mechanisms, and (2) spatiotemporal dynamics of Ca²⁺ signalling in cardiac and vascular function and remodelling. We also identify conceptual and technical challenges that must be addressed to accelerate therapeutic discovery and emphasize cross-cutting opportunities where experimental and computational approaches can converge. By integrating ion channel biology and Ca²⁺ signalling mechanisms across scales, this work outlines new directions for advancing cardiovascular research and treatment.

Zebrafish rapidly acquire new locomotor movements during the first few days of development. Rapid, ballistic movements relying on early-born primary motoneurons are supplemented with slower, more co-ordinated movements relying on later-born secondary motoneurons. We demonstrate distinct developmental dynamics of two persistent ionic currents related to locomotor rhythmogenesis in primary motoneurons during early development. From 2 to 5 days post-fertilization (dpf), a riluzole-sensitive persistent inward Na⁺ current associated with neural excitability gradually decreases in primary motoneurons. By contrast, the persistent outward potassium M-current peaks at 3 dpf and decreases afterwards. The influence of the M-current on the excitability and spike-frequency adaptation of primary motoneurons mirrors the non-monotonic developmental dynamics of its magnitude. Paired motoneuron-motor nerve recordings show different recruitment patterns of primary motoneurons at 3 vs. 5 dpf during light-evoked motor responses despite receiving similar synaptic drive. Modulation of the M-current during these responses shows that the M-current peak at 3 dpf shapes the activity pattern of primary motoneurons and consequent motor output. These findings thus reveal that rapid and precise changes in the intrinsic properties of spinal neurons enable motor control to mature appropriately in developing animals. KEY POINTS: Primary motoneurons express a persistent outward potassium current (M-current), as well as a persistent sodium current (I_NaP). During development, from 2 to 5 days post-fertilization (dpf), the amplitude of the persistent sodium current decreases. Across the same developmental period, the amplitude of the M-current increases transiently at 3 dpf before subsequently decreasing. As a consequence of these developmental changes, spike frequency adaptation and sustained firing in primary motoneurons changes between 2 and 5 dpf. The activity of primary motoneurons during light-evoked swimming is different between 3 and 5 dpf as a result of the changes in amplitude of the M-current.

The resting membrane potential (V_M) of vascular cells is a key determinant of arterial tone, integrating multiple ionic conductances to control smooth muscle contractility and endothelial signalling. In the human pulmonary circulation, the specific K⁺ channels responsible for setting the V_M of smooth muscle cells (SMCs) and endothelial cells (ECs) remain incompletely defined. This study investigated whether inwardly rectifying (Kir2) and ATP-sensitive (K_ATP) K⁺ channels are functionally expressed in native human pulmonary artery (PA) SMCs and ECs and assessed their contribution to vascular tone. Combining patch-clamp electrophysiology, immunofluorescence and wire myography, we evaluated channel expression and function in freshly isolated PASMCs and PAECs, and intact PAs. Kir2 channels were identified by Ba²⁺-sensitive inward currents with a characteristic rectification profile, supported by immunolabelling of Kir2.1 and Kir2.2 subunits. Functionally, BaCl₂ induced concentration-dependent contractions of PA rings and significantly attenuated acetylcholine-evoked, endothelium-dependent relaxation, revealing a tonic vasodilatory role for Kir2 channels. K_ATP currents, activated by pinacidil and blocked by glibenclamide and PNU-37883A, were also observed in PASMCs and PAECs, consistent with immunodetection of Kir6.1 and SUR2 subunits. In isolated PAs, pinacidil elicited concentration-dependent vasodilatation, which was significantly reduced by K_ATP channel blockade. Collectively, these findings demonstrate for the first time the functional presence of Kir2 and K_ATP channels in native human pulmonary vascular cells, and their modulatory role on V_M and arterial tone. These channels emerge as key electro-metabolic regulators of pulmonary vascular function and promising therapeutic targets in diseases characterized by V_M dysregulation, such as pulmonary arterial hypertension. KEY POINTS: Inwardly rectifying (Kir2) K⁺ channels are key regulators of the resting membrane potential (V_M) in different vascular cell types across multiple vascular beds, whereas ATP-sensitive (K_ATP) K⁺ channels detect changes in the metabolic state of vascular cells and translate these changes into V_M modulation. Despite their well-established physiological relevance, a comprehensive characterization of Kir2 and K_ATP channels in freshly isolated human pulmonary vascular cells - particularly within the endothelium - remains lacking. Our study provides compelling evidence for the functional expression of Kir2 and K_ATP channels in native human pulmonary arterial smooth muscle and endothelial cells, demonstrating their contribution to V_M regulation and pulmonary vascular tone at rest and in response to specific stimuli.

Abnormal placental angiogenesis contributes significantly to fetal growth restriction (FGR) and related complications. Methionine adenosyl-transferase 2A (MAT2A) can regulate the process of embryonic development; however, the role of MAT2A in placental angiogenesis during fetal development remains poorly understood. In this study, placentas from paired normal birth weight (NBW) and FGR piglets were used to quantify placental vascular density and biochemical indexes, while porcine trophoblast cells (pTrs) and porcine vascular endothelial cells (PVECs) were used to investigate the regulatory mechanism of MAT2A on placental angiogenesis. Here, we found that FGR placentas exhibited reduced vascular density and increased glycogen levels. Moreover, FGR placentas showed reduced S-adenosylmethionine (SAM) levels and downregulated protein expression of MAT2A and CD31. Placental SAM levels were positively correlated with vascular density, while MAT2A expression was positively correlated with CD31 expression. Further study showed that MAT2A knockdown disrupted the metabolism of methionine, glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation, and hindered protein synthesis, thereby impairing cell proliferation and migration in pTrs and/or PVECs, and inhibited angiogenesis in a co-culture system. In contrast, SAM supplementation promoted phosphorylation of ribosomal protein S6 kinase 1 (S6K1), downstream of the mammalian target of rapamycin complex 1 signalling pathway, and upregulated vascular endothelial growth factor-A protein expression, thereby increasing endothelial cell tube formation. In conclusion, our study demonstrates the potential of MAT2A in interventional therapy for placental development of FGR. KEY POINTS: Placental vascular density is correlated with decreased S-adenosylmethionine (SAM) levels caused by downregulated adenosyl-transferase 2A (MAT2A) expression. MAT2A regulates the placental mTORC1 signalling pathway and protein synthesis. MAT2A knockdown disrupts methionine metabolism, glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. MAT2A regulates the proliferation and migration capacity of placental trophoblast and endothelial cells. MAT2A regulates placental angiogenesis via the SAM-mTORC1-S6K1-VEGF-A signalling pathway.