Aims Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Vascular remodelling of pulmonary arteries, characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a hallmark of PAH. Here, we aimed to systematically characterize coagulation-independent effects of key coagulation proteases thrombin and Factor Xa (FXa) and their designated receptors, protease-activated receptor (PAR)-1 and -2, on PASMCs in vitro and experimental PAH in vivo. Methods and results In human and murine PASMCs, both thrombin and FXa were identified as potent mitogens, and chemoattractants. FXa mediated its responses via PAR-1 and PAR-2, whereas thrombin signalled through PAR-1. Extracellular-signal regulated kinases 1/2, protein kinase B (AKT), and sphingosine kinase 1 were identified as downstream mediators of PAR-1 and PAR-2. Inhibition of FXa or thrombin blunted cellular responses in vitro, but unexpectedly failed to protect against hypoxia-induced PAH in vivo. However, pharmacological inhibition as well as genetic deficiency of both PAR-1 and PAR-2 significantly reduced vascular muscularization of small pulmonary arteries, diminished right ventricular systolic pressure, and right ventricular hypertrophy upon chronic hypoxia compared to wild-type controls. Conclusion Our findings indicate a coagulation-independent pathogenic potential of thrombin and FXa for pulmonary vascular remodelling via acting through PAR-1 and PAR-2, respectively. While inhibition of single coagulation proteases was ineffective in preventing experimental PAH, our results propose a crucial role for PAR-1 and PAR-2 in its pathobiology, thus identifying PARs but not their dedicated activators FXa and thrombin as suitable targets for the treatment of PAH.
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Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, JapanTohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
Oe, Yuji
Hayashi, Sakiko
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Tohoku Univ, Grad Sch Pharmaceut Sci, Div Clin Pharmacol & Therapeut, Sendai, Miyagi 9808578, Japan
Fac Pharmaceut Sci, Sendai, Miyagi, JapanTohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
Hayashi, Sakiko
Fushima, Tomofumi
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Tohoku Univ, Grad Sch Pharmaceut Sci, Div Clin Pharmacol & Therapeut, Sendai, Miyagi 9808578, Japan
Fac Pharmaceut Sci, Sendai, Miyagi, JapanTohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
Fushima, Tomofumi
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Sato, Emiko
Kisu, Kiyomi
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Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, JapanTohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
Kisu, Kiyomi
Sato, Hiroshi
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Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
Tohoku Univ, Grad Sch Pharmaceut Sci, Div Clin Pharmacol & Therapeut, Sendai, Miyagi 9808578, Japan
Fac Pharmaceut Sci, Sendai, Miyagi, JapanTohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
Sato, Hiroshi
Ito, Sadayoshi
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Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, JapanTohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi, Japan
机构:Univ N Carolina, Sch Med, Div Hematol Oncol, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
McEachron, Troy A.
Pawlinski, Rafal
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Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USAUniv N Carolina, Sch Med, Div Hematol Oncol, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
Pawlinski, Rafal
Richards, Kristy L.
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Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USAUniv N Carolina, Sch Med, Div Hematol Oncol, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
Richards, Kristy L.
Church, Frank C.
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Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USAUniv N Carolina, Sch Med, Div Hematol Oncol, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
Church, Frank C.
Mackman, Nigel
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Univ N Carolina, Sch Med, Div Hematol Oncol, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USAUniv N Carolina, Sch Med, Div Hematol Oncol, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA