Cavopulmonary anastomosis induces pulmonary expression of the angiotensin II receptor family

Abstract

Background: Cavopulmonary anastomosis is used for palliation of cyanotic cardiac lesions. Postoperative development of pulmonary arteriovenous malformations can be significant in 10% to 25% of patients. To study the basis for formation of arteriovenous malformations, we developed an ovine model that reliably induces their development 8 weeks after cavopulmonary anastomosis. Previously, we found that cavopulmonary anastomosis inhibits the expression of pulmonary angiotensin-converting enzyme and suppresses angiotensin II production. Objective: This study examines the role of the angiotensin II receptors, type 1 and type 2, in this setting of pulmonary vascular remodeling. Methods: Lambs, aged 40 to 50 days, underwent cavopulmonary anastomosis. In age-matched control animals, a sham operation was performed. Messenger RNA and protein expression in lung specimens was measured at successive time points after cavopulmonary anastomosis or sham operations (n = 3 at each time point). Results: Angiotensin type 1 mRNA was maximally upregulated 2-fold at 5 weeks after cavopulmonary anastomosis (P =. 006). Expression of angiotensin type 1 protein was increased at least 2-fold at 2, 5, and 15 weeks after cavopulmonary anastomosis (P =. 005). Cavopulmonary anastomosis also increased angiotensin type 2 mRNA and protein expression at least 2-fold at 2 and 5 weeks (P =. 02) after surgical intervention. At 15 weeks, expression of angiotensin type 2 mRNA and protein was unchanged from that seen in control animals. Immunolocalization in pulmonary tissue sections 2 weeks after cavopulmonary anastomosis revealed markedly enhanced staining of angiotensin II receptor type 1 in vascular smooth muscle and angiotensin II receptor type 2 in the endothelium of pulmonary arteries. Conclusions: Rapid elevation in the expression of the type 1 and 2 angiotensin II receptors in the affected pulmonary vasculature after cavopulmonary anastomosis suggests their involvement in the pathologic vascular remodeling that occurs after cavopulmonary anastomosis.