Poster Presentation & Flash Talk 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Hydrogen sulphide protection against fetal origins of peripheral vascular disease (#118)

Bernardo J Krause 1 , Adolfo A Paz 1 , Tess AC Garrud 2 , Sage G Ford 2 , Youguo Niu 2 3 4 , Dino A Giussani 2 3 4
  1. Division of Pediatrics, Pontificia Universidad Catolica de Chile, Santiago, SANTIAGO, Chile
  2. Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
  3. Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
  4. Cambridge Cardiovascular Strategic Research Initiative, Cambridge, United Kingdom

Introduction: Developmental origins of cardiovascular disease remain an important problem, increasing interest in isolating mechanisms to identify intervention. Here, we tested the hypothesis using a chicken embryo model system that hydrogen sulphide (H2S), a cysteine-derived gasotransmitter, conveys direct protection to the developing cardiovascular system in adverse conditions.

 Methods: Fertilised Bovans Brown eggs were incubated under normoxia (Nx, n=14) or hypoxia (Hx, 14% O2, n=16) from day 1 (term ~ 21 d). The H2S precursor N-acetylcysteine (NAC, 33 μg.kg-1) or vehicle (saline) was administered daily into the air cell from day 13, equating to 25 weeks of human pregnancy. On day 19, following euthanasia, the embryo was weighed and second order femoral arteries mounted for wire-myography. Responses to SNP (10-9-10-4M), the H2S donor NaHS (10-6-10-4M) and methacholine (1010-10-5M) were generated; the latter + LNAME (10-5M) to isolate NO-dependent and -independent mechanisms. Expression of H2S- (CSE, CBS) synthesising enzymes were determined in aorta by qPCR. Data were analysed by Two-Way ANOVA.

Results: Hypoxic development promoted NO-dependent endothelial dysfunction in the term chicken embryo (Fig. 1A and B). Treatment with NAC following the onset of hypoxic incubation rescued endothelial dysfunction via enhanced NO-independent mechanisms (Fig.1A and B). Embryos treated with NAC, whether normoxic or hypoxic, showed enhanced relaxant responses to NaHS (Fig.1C). Hypoxic chicken embryos, with or without NAC, showed a markedly increased vascular expression of CSE compared with normoxic embryos (Fig.1D).   

Conclusions: The gasotransmitter H2S appears an excellent candidate for therapy against developmental origins of peripheral vascular disease.

 Supported by SRI In-Training Grant, Fondecyt 1181341, The Wellcome Trust and The British Heart Foundation

 

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Figure 1. Values are mean ± SEM, *p < 0.05, **p < 0.01 & ***p < 0.01, vs. Nx-control; †p < 0.05 vs. Hx-control; ɸp < 0.05 vs. Nx-NAC (ANOVA).