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Maternal-pup interaction disturbances induce long-lasting changes in the newborn rat pulmonary vasculature
Yulia Shifrin1, Sina Sadeghi1, Jingyi Pan1
1Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and.
Insights
Neonatal stress from fostering can cause lasting pulmonary vascular changes in rats. This includes reduced blood vessel relaxation and remodeling, influenced by the renin-angiotensin system.
Area of Science:
- Physiology
- Neonatology
- Vascular Biology
Background:
- Pulmonary vascular resistance can remain high postnatally due to unknown factors.
- Neonatal stressors are implicated in long-term vascular and behavioral changes.
- Cross-fostering is a model to study the impact of early-life stress.
Purpose of the Study:
- To investigate if fostering newborn rats leads to persistent pulmonary vascular changes into adulthood.
- To compare pulmonary vascular function and structure in fostered rats versus those raised by biological mothers.
Main Methods:
- Rats were cross-fostered or raised by biological mothers.
- Pulmonary vascular function was assessed at 14 days of age (adulthood).
- Evaluations included endothelium-dependent relaxation, gene expression (e.g., nitric oxide synthase, ANG II receptor type 1), and vascular remodeling.
Main Results:
- Fostered rats had reduced maternal-pup contact and impaired pulmonary arterial relaxation.
- Downregulation of endothelial nitric oxide synthase and tetrahydrobiopterin deficiency were observed.
- Increased ANG II receptor type 1 expression, pulmonary vascular remodeling, and right ventricular hypertrophy persisted into adulthood.
- Adult fostered rats showed heightened pulmonary artery contraction to ANG II and thromboxane A2.
Conclusions:
- Fostering-induced neonatal stress results in enduring pulmonary vascular alterations.
- These changes are mediated through the renin-angiotensin system.
- Early-life stress impacts long-term cardiovascular health.
Abstract:
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.
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