The functional role of bestrophins and TMEM16A in rat mesenteric small arteries

Two Ca 2+ ‐activated Cl − currents ( I Cl(Ca) ) are present in vascular smooth muscle (VSMC). One is cGMP dependent, the other is characterized as a classical I Cl(Ca) . Here we downregulate bestrophin‐3 (best3) and TMEM16A, to assess their importance for the two I Cl(Ca) and for the role of I Cl(Ca) in vascular function. Best3 and TMEM16A were downregulated in rat small mesenteric arteries using siRNA. Knockdown was confirmed at mRNA and protein levels 3 days after transfection. Best3 downregulation suppressed the cGMP‐dependent I Cl(Ca) while TMEM16A downregulation suppresed both I Cl(Ca) s. Both best3 and TMEM16A downregulation suppressed oscillations in vascular tone i.e. vasomotion. Best3 downregulation was without effect on sensitivity and maximal force production to norepinephrine while TMEM16A downregulation significantly reduced both. Also the force production to 125 mM KCl was reduced by TMEM16A downregulation. We conclude that TMEM16A is essential for both I Cl(Ca) s while best3 may be modifying the TMEM16A current characteristics in a subset of channels. The cGMP‐dependent I Cl(Ca) is critical for vasomotion and normal expression of TMEM16 is essential for VSMC conctractility.