{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:57:45Z","timestamp":1791320265183,"version":"4.3.1"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2001,8,14]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Background<\/jats:italic>\n                <\/jats:bold>\n              <\/jats:italic>\n            <\/jats:bold>\n            Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-\u03b2 (TGF-\u03b2) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-\u03b2 superfamily members.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Methods and Results<\/jats:italic>\n                <\/jats:bold>\n              <\/jats:italic>\n            <\/jats:bold>\n            For studies of\n            <jats:sup>3<\/jats:sup>\n            H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-\u03b2\n            <jats:sub>1<\/jats:sub>\n            (10 ng\/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng\/mL) inhibited basal and serum-stimulated\n            <jats:sup>3<\/jats:sup>\n            H-thymidine incorporation, and TGF-\u03b2\n            <jats:sub>1<\/jats:sub>\n            and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-\u03b2\n            <jats:sub>1<\/jats:sub>\n            stimulated\n            <jats:sup>3<\/jats:sup>\n            H-thymidine incorporation (200%;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription\u2013polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-\u03b2RI, Alk-1, ActRI, and BMPRIB) and type II (TGF-\u03b2RII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with\n            <jats:sup>125<\/jats:sup>\n            I-TGF-\u03b2\n            <jats:sub>1<\/jats:sub>\n            confirmed that the abnormal responses in PPH cells were not due to differences in TGF-\u03b2 receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-\u03b2RII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Conclusions<\/jats:italic>\n                <\/jats:bold>\n              <\/jats:italic>\n            <\/jats:bold>\n            We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-\u03b2\n            <jats:sub>1<\/jats:sub>\n            and BMPs and that altered integration of TGF-\u03b2 superfamily growth signals may contribute to the pathogenesis of PPH.\n          <\/jats:p>","DOI":"10.1161\/hc3201.094152","type":"journal-article","created":{"date-parts":[[2007,9,28]],"date-time":"2007-09-28T18:31:09Z","timestamp":1191004269000},"page":"790-795","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":394,"title":["Altered Growth Responses of Pulmonary Artery Smooth Muscle Cells From Patients With Primary Pulmonary Hypertension to Transforming Growth Factor-\u03b2\n            <sub>1<\/sub>\n            and Bone Morphogenetic Proteins"],"prefix":"10.1161","volume":"104","author":[{"given":"Nicholas W.","family":"Morrell","sequence":"first","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Upton","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen B.","family":"Jourdan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal","family":"Morgan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen K.","family":"Sheares","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Trembath","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke\u2019s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199701093360207"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.80.5.2805258"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65137-1"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.3.9906051"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-277"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/79226"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/303059"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.37.10.741"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6101(96)00048-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6101(99)00034-9"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.59.1.89"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119754"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006323200"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(200007)184:1<37::AID-JCP4>3.0.CO;2-M"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119830"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1999.277.3.L440"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199606)167:3<394::AID-JCP3>3.0.CO;2-K"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118333"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1086\/513903"},{"key":"e_1_3_3_20_2","unstructured":"BMPR2 Primer sequences. 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