{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:26:54Z","timestamp":1791210414611,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,4,27]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>In the present study we investigated the importance of protease-activated receptor (PAR)\u20132 and its ligand mast cell tryptase in the development of PH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)\u2013treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)\u2013BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)\u20131\u03b1 depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2- and ERK1\/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Our study identified a novel role of PAR-2 in vascular remodeling in the lung. Interference with this pathway may offer novel therapeutic options for the treatment of PH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.111.257568","type":"journal-article","created":{"date-parts":[[2012,3,30]],"date-time":"2012-03-30T00:42:00Z","timestamp":1333068120000},"page":"1179-1191","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":70,"title":["PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension"],"prefix":"10.1161","volume":"110","author":[{"given":"Grazyna","family":"Kwapiszewska","sequence":"first","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Markart","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhola Kumar","family":"Dahal","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baktybek","family":"Kojonazarov","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh Matthew","family":"Marsh","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph Theo","family":"Schermuly","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Taube","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Meinhardt","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein Ardeschir","family":"Ghofrani","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Steinhoff","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus Theo","family":"Preissner","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Olschewski","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Weissmann","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K., L.M.M., A.O.); Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, The Netherlands (C.T.); Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Wygrecka","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine (G.K., P.M., B.K.D., B.K., R.T.S., H.A.G., W.S., N.W.), Anatomy (A.M.), and Biochemistry (K.T.P., M.W.), University of Giessen Lung Centre, Giessen, Germany; 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