We have previously shown Twik‐2 −/− mice develop pulmonary hypertension and vascular remodeling. We hypothesized that distal pulmonary arteries (D‐ PAs) 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 ( PASMCs) 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‐ PAs and D‐ PAs 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‐ PAs under arterial conditions. Under venous conditions, Twik‐2 −/− RM‐ PAs showed an increased sensitivity to PE with a lower EC50 ( P = 0.02). Under venous conditions, Twik‐2 −/− D‐ PAs showed an increase maximal vasoconstrictor response to both phenylephrine and U46619 compared to the WT mice ( P < 0.05). Isolated PASMCs from Twik‐2 −/− D‐ PA were depolarized and had higher intracellular calcium levels compared to PASMCs 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‐ PAs may contribute to pulmonary hypertensive vasculopathy.