Key result
Col4a2 mutation impairs cerebral myogenic tone in aged mice via PKA-dependent RyR2 remodeling.
Why the study?
The signaling mechanisms that precede vascular damage in cerebral small vessel disease caused by COL4A1 and COL4A2 pathogenic variants remain incompletely defined.
Age-associated, PKA-dependent remodeling of RyR2 clusters is identified as a novel mechanism driving cerebral arterial dysfunction in a COL4A2 mutation model.
Age-dependent pial artery dysfunction in Col4a2 mice; leaves open mechanisms preceding hemorrhage and human translation.
Pathogenic variants of COL4A1 and COL4A2 , which encode the α1 and α2 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 Ca 2+ signals (Ca 2+ sparks) generated by the release of Ca 2+ through ryanodine receptors (RyR2s) on the sarcoplasmic reticulum (SR) was increased, and large-conductance Ca 2+ -activated K + (BK) channel activity was elevated, in cerebral pial artery smooth muscle cells (SMCs) from aged Col4a2 +/G646D mice. SR Ca 2+ 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.
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Lavanderos et al. (2026) studied COL4A2-related disease. Col4a2 +/G646D mutation vs. Controls was evaluated on Cerebral arterial function and pressure-induced myogenic tone. The Col4a2 +/G646D mutation in aged mice caused impaired cerebral pial artery myogenic tone driven by PKA-dependent nanoscale remodeling of RyR2 clusters.
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