Twik‐2 −/− mouse demonstrates pulmonary vascular heterogeneity in intracellular pathways for vasocontractility

We have previously shown Twik‐2 −/− mice develop pulmonary hypertension and vascular remodeling. We hypothesized that distal pulmonary arteries (D‐ PA s) of the Twik‐2 −/− mice are hypercontractile under physiological venous conditions due to altered electrophysiologic properties between the conduit and resistance vessels in the pulmonary vascular bed. We measured resting membrane potential and intracellular calcium through Fura‐2 in freshly digested pulmonary artery smooth muscles ( PASMC s) from both the right main ( RM ‐ PA ) and D‐ PA (distal) regions of pulmonary artery from WT and Twik‐2 −/− mice. Whole segments of RM ‐ PA s and D‐ PA s from 20 to 24‐week‐old wildtype ( WT ) and Twik‐2 −/− mice were also pressurized between two glass micropipettes and bathed in buffer with either arterial or venous conditions. Abluminally‐applied phenylephrine ( PE ) and U46619 were added to the buffer at log increments and vessel diameter was measured. All values were expressed as averages with ± SEM . Vasoconstrictor responses did not differ between WT and Twik‐2 −/− RM ‐ PA s under arterial conditions. Under venous conditions, Twik‐2 −/− RM ‐ PA s showed an increased sensitivity to PE with a lower EC 50 ( P  = 0.02). Under venous conditions, Twik‐2 −/− D‐ PA s showed an increase maximal vasoconstrictor response to both phenylephrine and U46619 compared to the WT mice ( P  < 0.05). Isolated PASMC s from Twik‐2 −/− D‐ PA were depolarized and had higher intracellular calcium levels compared to PASMC s from RM ‐ PA of both WT and Twik‐2 −/− mice. These studies suggest that hypercontractile responses and electrophysiologic properties unique to the anatomic location of the D‐ PA s may contribute to pulmonary hypertensive vasculopathy.