Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 289; no. 6; pp. H2334 - H2341
• Main Authors: Lam, Chen-Fuh, Peterson, Timothy E, Croatt, Anthony J, Nath, Karl A, Katusic, Zvonimir S
• Format: Journal Article
• Language: English
• Published: United States 01.12.2005
• Subjects: Animals; Blood Flow Velocity; Blood Pressure; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Neovascularization, Pathologic - etiology; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - physiopathology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Rats; Rats, Sprague-Dawley; Vasoconstriction
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00375.2005

Departments of 1 Anesthesiology and 2 Molecular Pharmacology and Experimental Therapeutics, and 3 Division of Nephrology, Mayo Clinic College of Medicine, Rochester, Minnesota Submitted 17 April 2005 ; accepted in final form 7 June 2005 Patients with left-to-right shunt congenital heart disease may develop pulmonary hypertension. Perioperative mortality of these patients is high due to abnormal vasoreactivity of the pulmonary artery (PA). We studied the changes in the PA induced by high pulmonary blood flow in rats with aortocaval fistula. Eight weeks after surgery, morphological changes of the PA were studied and vasomotor function was assessed by isometric force recording. Expression of endothelial nitric oxide (NO) synthase (eNOS), VEGF, and cyclooxygenase-2 (COX-2) proteins and levels of cGMP in the PA were analyzed. Rats with high pulmonary blood flow developed pulmonary hypertension, medial thickening, and increasing of internal elastic lamina and basement membrane in the PA. When compared with sham-operated animals, rats with fistula had significantly increased contractions in the PA, whereas relaxations to acetylcholine and NO donor were reduced. Concentrations of cGMP were reduced in the PA of rats with pulmonary hypertension (18.4 ± 3.3 vs. 9.4 ± 1.7 pmol/mg protein; P = 0.04). The altered vasomotor function was normalized by treatment with indomethacin. The PA of rats with fistula expressed higher levels of eNOS, phosphorylated eNOS, and COX-2. Sustained high PA blood flow in rats causes pulmonary hypertension that is morphologically and functionally identical with patients with flow-induced pulmonary hypertension. Abnormal vasomotor function of the PA in these animals appears to be mediated by reduced availability and the biological effect of endogenous NO and the high production of vasoconstrictor prostanoids. Increased eNOS and phosphorylated eNOS are most likely the adaptive changes in response to an increase in PA pressure secondary to high blood flow. guanosine 3',5'-cyclic monophosphate; cyclooxygenase-2; endothelium; endothelial nitric oxide synthase Address for reprint requests and other correspondence: Z. S. Katusic, Dept. of Anesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail katusic.zvonimir{at}mayo.edu )