Maternal-pup interaction disturbances induce long-lasting changes in the newborn rat pulmonary vasculature.
The factors accounting for the pathological maintenance of a high pulmonary vascular (PV) resistance postnatally remain elusive, but neonatal stressors may play a role in this process. Cross-fostering in the immediate neonatal period is associated with adult-onset vascular and behavioral changes, likely triggered by early-in-life stressors. In hypothesizing that fostering newborn rats induces long-lasting PV changes, we evaluated them at 14 days of age during adulthood and compared the findings with animals raised by their biological mothers. Fostering resulted in reduced maternal-pup contact time when compared with control newborns. At 2 wk of age, fostered rats exhibited reduced pulmonary arterial endothelium-dependent relaxation secondary to downregulation of tissue endothelial nitric oxide synthase expression and tetrahydrobiopterin deficiency-induced uncoupling. These changes were associated with neonatal onset-increased ANG II receptor type 1 expression, PV remodeling, and right ventricular hypertrophy that persisted into adulthood. The pulmonary arteries of adult-fostered rats exhibited a higher contraction dose response to ANG II and thromboxane A2, the latter of which was abrogated by the oxidant scavenger Tempol. In conclusion, fostering-induced neonatal stress induces long-standing PV changes modulated via the renin-angiotensin system.
Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and.
Yulia
Y
Shifrin
Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and.
Sina
S
Sadeghi
Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and.
Jingyi
J
Pan
Department of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada.
Amish
A
Jain
Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and.
Andres F
AF
Fajardo
Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and Department of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada.
Patrick J
PJ
McNamara
Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and Department of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada jaques.belik@sickkids.ca.
Jaques
J
Belik
D000818:Animals; D000831:Animals, Newborn; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D008168:Lung / Q000098:blood supply* / Q000201:enzymology; D008425:Maternal Behavior; D009119:Muscle Contraction; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System; D013315:Stress, Psychological / Q000503:physiopathology; D014655:Vascular Resistance
D017382:Reactive Oxygen Species; D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C003402:sapropterin
neonatal stressors; pulmonary vasomotor tone; renin angiotensin system