Role of neutral sphingomyelinase in the pulmonary vascular regulation during postnatal development and chronic hypoxia.

Carmen Menéndez1, Jaques Belik2, Jingyi Pan2, Bianca Barreira1, Enrique Moreno1, Angel Cogolludo1, Jane A. Mitchell3, Francisco Pérez-Vizcaíno1, Laura Moreno1,3. 1Department of Pharmacology, Universidad Complutense de Madrid and Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain, 2Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, University of Toronto, Toronto, Canada, 3Cardiothoracic Pharmacology, NHLI, Imperial College, London, UK.

At birth and during the first days of postnatal life, profound adaptive processes occur in the lung to accommodate the increased pulmonary blood flow and the gas exchange transition from the placenta to the alveoli. The failure or reversal of this adaptive process can lead to the persistent pulmonary hypertension of the neonate syndrome (PPHN). Recently, we demonstrated that neutral sphingomyelinase (nSMase; SMPD3) plays a crucial role in the signaling cascade of hypoxic pulmonary vasoconstriction (Cogolludo et al., 2009). The aim of this study was to analyze the role of nSMase during pulmonary postnatal development and following chronic hypoxia exposure in the neonatal period.

C57/Bl6 newborn (<6 hours) mice were randomly placed into normoxic (21% O2) or normobaric hypoxic (13% O2) chambers for 1 or 2 weeks. Adult C57/BL6 mice (8-10 weeks-old) were used for comparison. Mice were killed by cervical dislocation and vascular reactivity was assessed using intrapulmonary arteries mounted into isometric wire myographs. Lung mRNA levels were analysed by real time PCR.

Table 1. Developmental changes in pulmonary vascular function and gene expression. EMAX, Maximal effects induced by vasoactive factors in isolated pulmonary arteries. Data are shown as mean ± S.E.M. of n = 4-9. * and # p<0.05 by one way ANOVA followed by Bonferroni post hoc test compared to 1-week-old normoxic or normoxic age-matched groups, respectively.

The contractile responses to the thromboxane A2 mimetic U46619 (1nM - 1µM) increased with postnatal age alongside the increase in pulmonary relaxation to endothelium-dependent (acetylcholine; ACh: 1nM - 100µM) and endothelium-independent (sodium nitroprusside; SNP: 1nM – 10µM) vasodilators. (Table 1). These changes in vascular reactivity were accompanied by an increase in the expression of BMPRII and nSMase. Exposure to chronic hypoxia during the first 2 weeks of life decreased the expression levels of both proteins and prevented, at least partially, the maturation of pulmonary vascular function.

These results suggest that a maturational increase in the expression of BMPRII and nSMase occurs in parallel to changes in pulmonary vascular function and that these processes are disrupted by chronic hypoxia.

Cogolludo et al.(2009). Cardiovasc Res: 82:296-302.

Supported by Spanish MICINN (FPI, Juan de la Cierva), Marie Curie Reintegration grant and Young Research Award Agreement from Pfizer.