Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice.
Perinatal adverse events such as limitation of nutrients or oxygen supply are associated with the occurrence of diseases in adulthood, like cardiovascular diseases and diabetes. We investigated the long-term effects of perinatal hypoxia on the lung circulation, with particular attention to the nitric oxide (NO)/cGMP pathway. Mice were placed under hypoxia in utero 5 days before delivery and for 5 days after birth. Pups were then bred in normoxia until adulthood. Adults born in hypoxia displayed an altered regulation of pulmonary vascular tone with higher right ventricular pressure in normoxia and increased sensitivity to acute hypoxia compared with controls. Perinatal hypoxia dramatically decreased endothelium-dependent relaxation induced by ACh in adult pulmonary arteries (PAs) but did not influence NO-mediated endothelium-independent relaxation. The M(3) muscarinic receptor was implicated in the relaxing action of ACh and M(1) muscarinic receptor (M(1)AChR) in its vasoconstrictive effects. Pirenzepine or telenzepine, two preferential inhibitors of M(1)AChR, abolished the adverse effects of perinatal hypoxia on ACh-induced relaxation. M(1)AChR mRNA expression was increased in lungs and PAs of mice born in hypoxia. The phosphodiesterase 1 (PDE1) inhibitor vinpocetine also reversed the decrease in ACh-induced relaxation following perinatal hypoxia, suggesting that M(1)AChR-mediated alteration of ACh-induced relaxation is due to the activation of calcium-dependent PDE1. Therefore, perinatal hypoxia leads to an altered pulmonary circulation in adulthood with vascular dysfunction characterized by impaired endothelium-dependent relaxation and M(1)AChR plays a predominant role. This raises the possibility that muscarinic receptors could be key determinants in pulmonary vascular diseases in relation to "perinatal imprinting."
Peyter
Anne-Christine
AC
Neonatal Research Laboratory, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Muehlethaler
Vincent
V
Liaudet
Lucas
L
Marino
Mathieu
M
Di Bernardo
Stefano
S
Diaceri
Giacomo
G
Tolsa
Jean-François
JF
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D043264:Phosphodiesterase I / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D043643:Receptor, Muscarinic M1; D014665:Vasodilator Agents; D009569:Nitric Oxide; D043264:Phosphodiesterase I; D006152:Cyclic GMP; D000109:Acetylcholine