AUTHOR=Kitagawa Melanie G. , Reynolds Julia O. , Wehrens Xander H. T. , Bryan Robert M. , Pandit Lavannya M. 

TITLE=Hemodynamic and Pathologic Characterization of the TASK-1−/− Mouse Does Not Demonstrate Pulmonary Hypertension

JOURNAL=Frontiers in Medicine

VOLUME=Volume 4 - 2017

YEAR=2017

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2017.00177

DOI=10.3389/fmed.2017.00177

ISSN=2296-858X

ABSTRACT=Pulmonary hypertension (PH) carries significant associated morbidity and mortality and the underlying molecular mechanisms of PH are not well understood.  Loss-of-function mutations in TASK-1 potassium channels are associated with PH in humans. Although TASK-1 has been considered in the development of PH for over a decade, characterization of TASK-1 knockout mice has been limited to in vitro studies or in vivo studies in room air at isolated time points. The purpose of this study was two-fold. First, we sought to determine if TASK -/- male and female mice developed PH over the span of one year. Second, we sought to determine the effect of chronic hypoxia, a stimulus for PH, and its recovery on PH in TASK-1 -/- mice.
We measured right ventricular systolic pressure (RVSP) and vascular remodeling in male and female C57BL/6 WT and TASK-1 -/- mice at separate time points:20 to 24 weeks and 1 year of age. Additionally, we measured RVSP and vascular remodeling in TASK-1 -/- and wildtype mice between 13 to 16 weeks of age exposed to 10% hypoxia for three weeks followed by recovery to room air conditions for an additional six weeks. 

Results: RVSP was similar between WT and TASK-/- mice. Male and female WT and TASK-1 -/- mice all demonstrated age-related increases in RVSP, which correlated to age-related vascular remodeling in male mice but not in female mice.  Male TASK-1 -/- and WT mice exposed to chronic hypoxia demonstrated increased RVSP which decreased following room air recovery. WT and TASK-1 -/- male mice demonstrated vascular remodeling upon exposure to hypoxia that persisted in room air recovery.

Conclusions: Female and male TASK-1 -/- mice do not develop hemodynamic or vascular evidence for PH, but RVSP rises in an age dependent manner independent of genotype. TASK-1-/- and WT male mice develop hypoxia-induced elevations in RVSP that decrease to baseline after recovery in room air. TASK-1-/- and WT male mice demonstrate vascular remodeling after exposure to hypoxia that persists despite recovery to room air conditions, and does not correlate with RVSP normalization.