Aging Cell · Mar 18, 2020

Age attenuates the T-type CaV 3.2-RyR axis in vascular smooth muscle

By Fan G, Kaßmann M, Cui Y et al.

Caveolae position CaV 3.2 (T-type Ca²⁺ channel encoded by the α-3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca²⁺ influx to trigger Ca²⁺ sparks and large-conductance Ca²⁺ -activated K⁺ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca²⁺ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Cav 3.2 channel inhibition by Ni²⁺ (50 µM) and caveolae disruption by methyl-ß-cyclodextrin or genetic abolition of Eps15 homology domain-containing protein (EHD2) inhibited Ca²⁺ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Cav 3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Cav 1.2-/- mice, caffeine (RyR activator) and thapsigargin (Ca²⁺ transport ATPase inhibitor), we found that sufficient SR Ca²⁺ load is a prerequisite for the CaV 3.2-RyR axis to generate Ca²⁺ sparks. We identified a fraction of Ca²⁺ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd³⁺ (100 µM), but insensitive to CaV 1.2 and CaV 3.2 channel blockade. Our data demonstrate that the VSMC CaV 3.2-RyR axis is down-regulated by aging. This defective CaV 3.2-RyR coupling is counterbalanced by a Gd³⁺ sensitive Ca²⁺ pathway providing compensatory Ca²⁺ influx for triggering Ca²⁺ sparks in aged VSMCs.

doi.org/10.1111/acel.13134Open accessPubMed 32187825Mechanisms