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Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow
Boaz Ovadia1, Olaf Reinhartz, Robert Fitzgerald
1Department of Pediatrics, University of California, San Francisco, 94143, USA.
Insights
Altered pulmonary vascular reactivity in congenital heart disease is linked to early changes in endothelin-1 (ET-1) signaling, not nitric oxide (NO), in lambs with increased pulmonary blood flow.
Area of Science:
- Pediatric Cardiology
- Vascular Biology
- Neonatal Physiology
Background:
- Congenital heart disease (CHD) with increased pulmonary blood flow causes significant morbidity and mortality in children.
- Pulmonary vascular reactivity is modulated by nitric oxide (NO) and endothelin-1 (ET-1).
- Early endothelial dysfunction may underlie altered vascular reactivity in CHD.
Purpose of the Study:
- To investigate endothelial function in a lamb model of increased pulmonary blood flow at one week of life.
- To determine the roles of NO and ET-1 signaling pathways in early vascular alterations.
Main Methods:
- Fetal lambs received an aortopulmonary vascular graft (shunt) in utero.
- Vascular reactivity was assessed using intravenous acetylcholine (ACh) and inhaled NO.
- Pulmonary tissue levels of NO(x), NO synthase (NOS) activity, ET-1, ET-converting enzyme-1, and ET(B) receptor were measured.
Main Results:
- Pulmonary vasodilator responses to ACh and NO were similar in shunted and control lambs.
- Responses to ET-1 and an ET(B) receptor agonist were attenuated in shunted lambs.
- Shunted lambs showed increased tissue ET-1, increased ET-converting enzyme-1, and decreased ET(B) receptor protein levels.
Conclusions:
- Increased pulmonary blood flow in early life alters endothelin-1 (ET-1) signaling before nitric oxide (NO) signaling.
- ET-1 plays an early role in the altered pulmonary vascular reactivity associated with congenital heart disease and increased pulmonary blood flow.
Abstract:
Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart disease and increased pulmonary blood flow. Nitric oxide (NO) and endothelin (ET)-1 are important mediators of pulmonary vascular reactivity. We hypothesize that early alterations in endothelial function contribute to the altered vascular reactivity associated with congenital heart disease. The objective of this study was to characterize endothelial function in our lamb model of increased pulmonary blood flow at 1 wk of life. Eleven fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 7 days after delivery. The pulmonary vasodilator response to both intravenous ACh (endothelium dependent) and inhaled NO (endothelium independent) was similar in shunted and control lambs. In addition, tissue NO(x), NO synthase (NOS) activity, and endothelial NOS protein levels were similar. Conversely, the vasodilator response to both ET-1 and 4Ala-ET-1 (an ET(B) receptor agonist) were attenuated in shunted lambs, and tissue ET-1 concentrations were increased (P < 0.05). Associated with these changes were an increase in ET-converting enzyme-1 protein and a decrease in ET(B) receptor protein levels (P < 0.05). These data demonstrate that increased pulmonary blood flow induces alterations in ET-1 signaling before NO signaling and suggest an early role for ET-1 in the altered vascular reactivity associated with increased pulmonary blood flow.