The mechanisms leading to elevations in precapillary pulmonary vascular resistance are complex and likely involve multiple pathways, but the histopathologic sequelae of these processes are restricted to a few findings, primarily neoangiogenesis, intimal and smooth muscle proliferation, vasoconstriction, and/or in situ thrombosis. Regardless of the etiology of pulmonary hypertension, abnormalities in endothelial function are often observed and likely play a central role in mediating structural changes.
Simonneau G. , Galie N., Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol.2004;43(suppl):5-12.
2.
Budhiraja R. , Tuder RM, Hassoun PMEndothelial dysfunction in pulmonary hypertension . Circulation. 2004 ; 109:159-165.
3.
Kasper M.Phenotypic characterization of pulmonary arteries in normal and diseased lung . Chest.2005;128(Suppl): 547S-552S.
4.
Keil A., Blom IE, Goldschmeding R., et al. Nitric oxide down-regulates connective tissue growth factor in rat mesangial cells. Kidney Int.2002;62:401-411.
5.
Emerson M., Momi S., Paul W., et al. Endogenous nitric oxide acts as a natural antithrombotic agent in vivo by inhibiting platelet aggregation in the pulmonary vasculature. Thromb Haemost.1999 ;81:961-966.
6.
Morris CR, Kate GJ, Poliakovic M., et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA.2005; 294:81-90.
7.
Morris CR, Morris SM Jr, Hagar W., et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease?Am J Respir Crit Care Med.2003;168:63-69.
8.
Mehta S., Stewart DJ, Langleben D., et al. Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation. 1995;92:1539-1545.
9.
Chou TF, Wu MS, Chien CT, et al. Enhanced expression of nitric oxide synthase in the early stage after increased pulmonary blood flow in rats. Eur J Cardiothorac Surg.2002;21:331-336.
10.
Giaid A., Saleh D.Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med.1995;333:214-221.
11.
Mason NA, Springall DR, Burke M., et al. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol.1998;185:313-318.
12.
Demoncheaux EA, Higenbottam TW, Kiely DG, et al. Decreased whole body endogenous nitric oxide production in patients with primary pulmonary hypertension. J Vasc Res.2005;42:133-136.
13.
Kielstein JT , Bode-Boger SM, Hesse G., et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2005;25:1414-1418.
14.
Galie N., Ghofrani HA, Torbicki A., et al. Sildenafil citrate therapy for pulmonary arterial hypertension . N Engl J Med.2005;353:2148-2157.
15.
Geraci MW, Gao B., Shepherd DC, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest.1999;103:1509-1515.
16.
Tahara N., Kai H., Niivama H., et al. Repeated gene transfer of naked prostacyclin synthase plasmid into skeletal muscles attenuates monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Hum Gene Ther.2004;15:1270-1278.
17.
Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med.1999;159:1925-1932.
18.
Christman BW , McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med.1992;327:70-75.
19.
Katugampola SD, Davenport APThromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT(1) receptor antagonist losartan. Br J Pharmacol.2001;134:1385-1392.
20.
Rich S., Hart K., Kieras K., et al. Thromboxane synthetase inhibition in primary pulmonary hypertension . Chest. 1987;91:356-360.
21.
Hassoun PM, Thappa V., Landman MJ, et al. Endothelin 1: mitogenic activity on pulmonary artery smooth muscle cells and release from hypoxic endothelial cells. Proc Soc Exp Biol Med.1992;199:165-170.
22.
Dupuis J.Endothelin-receptor antagonists in pulmonary hypertension. Lancet. 2001;358:1113-1114.
23.
Langleben D. , Dupuis J., Langleben I., et al. Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension. Chest. 2006;129:689-695.
24.
Giaid A., Yanagisawa M., Langleben D., et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med.1993;328:1732-1749.
25.
Galie N., Manes A., Branzi A.The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004; 61:227-237.
26.
Jasmin JF, Lucas M., Cernacek P., et al. Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation. 2001;103:314-318.
27.
Weir EK, Hong Z., Varghese A.The serotonin transporter: a vehicle to elucidate pulmonary hypertension?Circ Res.2004;94:1152-1144.
28.
Herve P., Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension . Am J Med.1995;99:249-254.
29.
Kramer MS, Lane DAAminorex, dexfenfluramine, and primary pulmonary hypertension. J Clin Epidemiol.1998; 51:361-364.
30.
Abenhaim L. , Moride Y., Brenot F., et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med.1996;335:609-616.
31.
Tuder RM, Flook BE, Voelkel NFIncreased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia: modulation of gene expression by nitric oxide. J Clin Invest.1995;95:1798-1807.
32.
Schermuly RT , Dony E., Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest.2005;115:2811-2821.
33.
Kakishita M. , Nishikimi T., Okano Y., et al. Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin Sci.1999;96:33-39.
Caramuru LH , Maeda NY, Bydlowski SP, et al. Age-dependent likelihood of in situ thrombosis in secondary pulmonary hypertension. Clin Appl Thromb Hemost. 2004;10:217-223.
36.
Herve P., Humbert M., Sitbon O., et al. Pathobiology of pulmonary hypertension: the role of platelets and thrombosis. Clin Chest Med.2001;22:451-458.
37.
Dresdale DT , Mitchom RJ, Schultz M.Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med.1954 ;30:195-207.
38.
Loyd JEGenetics and pulmonary hypertension. Chest.2002;122:284S-286S.
39.
Rich S., Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study . Ann Intern Med.1987;107:216-223.
40.
Grunig E., Mereles D., Arnold K., et al. Primary pulmonary hypertension is predominantly a hereditary disease. Chest.2002; 121 (Suppl): 81S-82S.
41.
Nichols WC, Koller DL, Slovis B., et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet.1997;15:277-280.
42.
Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in a TGF-β receptor, BMPR2, are the cause of familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet.2000;26:81-84.
43.
Newman JH, Trembath RC, Morse JA, et al. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol.2004;43(Suppl S):33S-39S.
44.
Elliott CGGenetics of pulmonary arterial hypertension: current and future implications . Semin Respir Crit Care Med.2005;26:365-371.
45.
Humbert M., Deng Z., Simonneau G., et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002; 20:518-523.
46.
Elliott CG, Glissmeyer EW, Havlena GT, et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation. 2006; 113:2509-2515.
