Pulmonary hypertension may develop in patients with left-to-right shunt congenital heart disease and systemic arteriovenous shunt. Abnormal vasoreactivity of pulmonary artery (PA) secondary to increased blood flow may responsible for the high perioperative mortality of these patients. Utilizing an aortocaval (AC) fistula, we studied the functional and morphological changes of PA in rats with chronic increased pulmonary blood flow.
Eight weeks after sham (n=8) or AC fistula (n=10) operation, PA of each rat was examined. Rings of second generation PA were contracted with phenylephrine (PE) in organ chambers. Concentration-response curves were obtained by cumulative addition of acetylcholine (Ach), and a nitric oxide (NO) donor (DEA-NONOate) to the pre-contracted rings. Protein expression and morphological changes of PA were examined.
Contractions to PE were significantly increased in the PA of rats with the AC fistula. Relaxation of PA to Ach was significantly impaired in the fistula rats with reduced maximal relaxation (96.9±0.9 versus 81.5±3.3%; P< 0.001). DEA-NONOate-induced relaxation of the PA was less affected in these rats. PA of fistula rats expressed higher levels of endothelial NO synthase (eNOS) and phosphorylated eNOS (ser1177). H&E and Verhoeff’s stains showed remarkable medial thickening of the PA, without significant changes in the intima. Thickening of internal elastic lamina and widening of subendothelial space with deposition of collagen fibers were found in the PA of rats with the fistula under an electron microscope.
Chronic increased blood flow causes vascular smooth muscle hypertrophy and enhances the contractility of PA. Endothelium-dependent relaxation is impaired in the PA with increased blood flow, while the endothelium-independent relaxation is preserved. Increased pulmonary blood flow also up-regulates the expressions of eNOS and phosphorylated eNOS in the PA. Remodeling in the subendothelium, which limits the diffusion of endothelium-released NO may responsible for the flow-induced vascular dysfunction of PA.
Subendothelium remodeling may lead to the vascular dysfunction of PA in patients with flow-induced pulmonary hypertension.
C. Lam, None.