Biology subjects

Sanchez Solano, A.

Publications and source records attributed to Sanchez Solano, A..

3 recordsLinked to original sources

bioRxiv2026

Ryanodine receptor cluster remodeling links COL4A2 mutation to cerebral artery dysfunction

Pathogenic variants of COL4A1 and COL4A2, which encode the 1 and 2 chains of type IV collagen in vascular basement membranes, cause cerebral small vessel disease and intracerebral hemorrhage, but the signaling mechanisms that precede vascular damage remain incompletely defined. Here, we investigated cerebral arterial function in mice heterozygous for the Col4a2+/G646D mutation. Cerebral pial arteries from aged (12-month-old), but not young (3-month-old), Col4a2+/G646D mice exhibited impaired pressure-induced myogenic tone, whereas downstream parenchymal arterioles retained normal myogenic responsiveness, revealing a segment-selective vascular defect. The frequency of subcellular Ca2+ signals (Ca2+ sparks) generated by the release of Ca2+ through ryanodine receptors (RyR2s) on the sarcoplasmic reticulum (SR) was increased, and large-conductance Ca2+-activated K+ (BK) channel activity was elevated, in cerebral pial artery smooth muscle cells (SMCs) from aged Col4a2+/G646D mice. SR Ca2+ store load and Ryr2 transcript abundance were unchanged in these cells, but Stimulated Emission Depletion super-resolution microscopy revealed that RyR2 protein clusters were enlarged compared with controls. Protein kinase A (PKA) activation reproduced RyR2 cluster enlargement, whereas PKA inhibition normalized RyR2 cluster organization and BK channel activity in SMCs from aged Col4a2+/G646D mice. These findings identify age-associated, PKA-dependent, nanoscale remodeling of RyR2 clusters as a previously unknown mechanism underlying cerebral arterial dysfunction in COL4A2-related disease.

physiology↗

bioRxiv2026

TRPM4 Couples Mechanical Force to Myogenic Constriction Throughout the Resistance Vasculature

BackgroundMyogenic tone is a fundamental property of resistance arteries that stabilizes tissue perfusion by coupling intraluminal pressure to smooth muscle cell (SMC) depolarization, Ca2+ influx, and vasoconstriction. TRPM4 (transient receptor potential melastatin 4) cation channels are required for this response in cerebral arteries, but whether TRPM4-dependent mechanotransduction is conserved across the broader resistance vasculature has remained unknown. MethodsWe combined droplet digital PCR, a newly generated Trpm4-Cre transgenic reporter mouse line, native-cell patch-clamp electrophysiology, pressure myography, selective pharmacological inhibition, and novel SMC-specific Trpm4-knockout (Trpm4-smKO) mice to define the expression, regulation, and functional importance of TRPM4 in cerebral, mesenteric, and skeletal muscle resistance arteries. ResultsTrpm4 transcripts were detected in all three vascular beds, and genetic reporter-based mapping localized TRPM4 expression to SMCs in multiple organs. Using conventional whole-cell patch-clamp electrophysiology, we recorded cation currents activated by high intracellular [Ca2+] and sensitive to the selective TRPM4 blocker 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA) in native SMCs from all three beds. In cells patch-clamped using the amphotericin B-perforated configuration, stretching the plasma membrane by applying negative pressure (-20 mmHg) through the patch pipette activated transient inward cation currents that were suppressed by NBA. The selective angiotensin II type 1 receptor (AT1R) blocker losartan also inhibited stretch-induced currents without affecting Ca2+-activated whole-cell TRPM4 currents, indicating that AT1R signaling is required for mechanotransduction in SMCs from all three vascular beds. In pressurized arteries with established myogenic tone, NBA produced reversible, concentration-dependent suppression of pressure-induced constriction of cerebral, mesenteric, and skeletal muscle arteries while sparing constriction induced by direct depolarization of SMCs with high (60 mM) extracellular [K+]. TRPM4-dependent whole-cell currents and stretch-induced cation currents were decreased in SMCs from Trpm4-smKO mice, and myogenic tone was essentially absent in all three vascular beds from these animals. ConclusionsThese findings show that TRPM4 is essential for pressure-induced SMC depolarization and myogenic constriction in the resistance vasculature.

physiology↗

bioRxiv2023

PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease

Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report a Col4a1 mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain capillary endothelial cells, leading to the loss of inwardly rectifier K+ (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP2 by converting it to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of aged Col4a1 mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD. One-sentence summaryPI3K inhibition rescues neurovascular coupling defects in cerebral small vessel disease.

neuroscience↗