• Direct regulation of cerebral artery contractility by simvastatin and rosuvastatin

      Zerin, Farzana; Pandey, A.; Hasan, A.; Menon, S.; Hasan, R. (2021)
      Statins are amongst the most widely prescribed drugs in the world with a range of vascular effects that have been primarily attributed to the inhibition of cholesterol and mevalonate biosynthesis, and the inhibition of mevalonate-dependent Rho/ROCK signaling upon long-term treatment. However, no studies have investigated the direct effects of acute statin application on fresh isolated resistance cerebral arteries using therapeutic concentrations of statins. Here, we examined acute vascular effects of therapeutically relevant concentrations of statins on male and female Sprague Dawley rat cerebral arteries and underlying molecular mechanisms using pressurized arterial myography as well as Ca2+ fluorescence and diameter measurement. Our data showed that the application of 1nM rosuvastatin and simvastatin constricted cerebral arteries within 2-3 minutes of drug application. The removal of extracellular Ca2+ with EGTA or the application of nimodipine, a selective blocker of smooth muscle cell voltage-gated Ca2+ channel, CaV1.2, each abolished cerebral artery vasoconstriction by statins, indicating that the Ca2+ entry through CaV1.2 plays a critical role here. Since Ca2+ entry into smooth muscle cells induces Ca2+ release from intracellular Ca2+ stores such as sarcoplasmic reticulum and endoplasmic reticulum. Altogether, our data suggests that smooth muscle cell CaV1.2 opening and Ca2+ influx is the primary mechanism underlying statin-induced constriction of cerebral arteries.