TY - JOUR
T1 - Classical transient receptor potential 1 and 6 contribute to hypoxic pulmonary hypertension through differential regulation of pulmonary vascular functions
AU - Xia, Yang
AU - Yang, Xiao Ru
AU - Fu, Zhenzhen
AU - Paudel, Omkar
AU - Abramowitz, Joel
AU - Birnbaumer, Lutz
AU - Sham, James S.K.
PY - 2014/1
Y1 - 2014/1
N2 - Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity, and vascular remodeling, which are associated with alterations in Ca homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries (PAs) of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (Trpc1 and Trpc6) mice compared with wild-type after exposure to 10% O2 for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic Trpc1 and Trpc6 mice. Small PAs of normoxic wild-type mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic Trpc1 PAs, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic Trpc6 PAs, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the augmented vasoreactivity was attenuated in Trpc1 and eliminated in Trpc6 PAs. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of microvessels were further suppressed in TRPC1-TRPC6 double-knockout mice. Our results, therefore, provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes, and that the presence of TRPC1 and TRPC6 is essential for the full development of hypoxic pulmonary hypertension in the mouse model.
AB - Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity, and vascular remodeling, which are associated with alterations in Ca homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries (PAs) of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (Trpc1 and Trpc6) mice compared with wild-type after exposure to 10% O2 for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic Trpc1 and Trpc6 mice. Small PAs of normoxic wild-type mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic Trpc1 PAs, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic Trpc6 PAs, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the augmented vasoreactivity was attenuated in Trpc1 and eliminated in Trpc6 PAs. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of microvessels were further suppressed in TRPC1-TRPC6 double-knockout mice. Our results, therefore, provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes, and that the presence of TRPC1 and TRPC6 is essential for the full development of hypoxic pulmonary hypertension in the mouse model.
KW - Hypertension, pulmonary
KW - Hypoxia
KW - TRPC1 channel
KW - TRPC6 channel
KW - Vascular smooth muscle
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U2 - 10.1161/HYPERTENSIONAHA.113.01902
DO - 10.1161/HYPERTENSIONAHA.113.01902
M3 - Article
C2 - 24144647
AN - SCOPUS:84891633620
SN - 0194-911X
VL - 63
SP - 173
EP - 180
JO - Hypertension
JF - Hypertension
IS - 1
ER -