Role of the endothelial caveolae microdomain in shear stress-mediated coronary vasorelaxation.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro cell culture and ex vivo tissue study with no human data
PubMed 28924052 · doi:10.1074/jbc.M117.786152
What was done
Freshly isolated bovine coronary endothelial cells (BCECs) and isolated coronary arterioles were evaluated to determine the role of caveolae, TRPV4 channels, and small-conductance calcium-activated potassium (SK/SK3) channels in shear stress-mediated vasodilation (SSD). Channel localization and interaction were assessed via co-immunoprecipitation with caveolin-1 antibodies. BCECs were exposed to acute (10 dynes/cm²) or prolonged (15 dynes/cm² for 16 h) shear stress, and channel currents, intracellular calcium ([Ca²⁺]ᵢ), nitric oxide, prostacyclin (PGI₂) production, and vascular diameter responses were evaluated using pharmacological inhibitors (HC067047 for TRPV4, apamin for SK) and agonists (GSK1016790A, isoproterenol).
What was found
TRPV4 and SK3 channels localized to caveolae and co-immunoprecipitated with caveolin-1. Acute shear stress activated both TRPV4 and SK currents; TRPV4 inhibition with HC067047 abolished shear stress-induced SK activation. In isolated coronary arterioles, apamin diminished SSD, whereas HC067047 caused shear stress to induce vasoconstriction. Prolonged shear stress increased NO and PGI₂ production and promoted TRPV4 translocation to caveolae. TRPV4 inhibition abolished shear stress-induced [Ca²⁺]ᵢ increases. The abstract reports directional changes without presenting numerical values, confidence intervals, or sample sizes.
Why it matters
This study identifies a molecular mechanism in vascular endothelial caveolae where mechanical shear stress triggers TRPV4-dependent SK3 channel activation, which is critical for coronary flow-mediated vasorelaxation.
Limits
The study is restricted to bovine cells and isolated vessels in an artificial flow environment; translational relevance to human coronary physiology is unverified. Exact sample sizes, statistical variance, and effect magnitudes are not provided in the abstract.
Cited by
- supports Vascular shear stress causes endothelial cells to secrete nitric oxide and prostacyclin, promoting vasodilation.