Published Online
on October 4, 2004

A more recent version of this article appeared on October 12, 2004

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Submitted on December 17, 2003
Revised on May 12, 2004
Accepted on May 19, 2004

Signaling Molecules in Overcirculation-Induced Pulmonary Hypertension in Piglets. Effects of Sildenafil Therapy

Benoit Rondelet MD, François Kerbaul MD, PhD, Ronald Van Beneden MSc, Sophie Motte DVM, Pierre Fesler MD, Ives Hubloue MD, Myriam Remmelink MD, PhD, Serge Brimioulle MD, PhD, Isabelle Salmon MD, PhD, Jean-Marie Ketelslegers MD, PhD, and Robert Naeije MD, PhD^*

From the Laboratory of Physiology, Faculty of Medicine, Free University of Brussels (B.R., F.K., S.M., P.F., I.H., S.B., R.N.); the Unit of Diabetes and Nutrition, Catholic University of Louvain, Brussels (R.V.B., J.-M.K.); and the Department of Pathology, Erasme Hospital, Free University of Brussels (M.R., I.S.), Belgium.

^* To whom correspondence should be addressed. E-mail: rnaeije{at}ulb.ac.be.

Background--The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH.

Methods and Results--Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20±2 to 33±1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II.

Conclusions--Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.

Key words: angiopoietins • heart defects • nitric oxide • remodeling • hypertension, pulmonary

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