Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life

Abstract

Background: We investigated the effects of fetal growth restriction (FGR) induced by maternal protein restriction on inflammatory vascular remodeling using a cuff-induced vascular injury mouse model.

Methods: Dams (C57BL/6J strain mice) were fed an isocaloric diet containing 20% protein (normal protein; NP) or 8% protein (low protein; LP) from 10 weeks of age until delivery. On the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed the NP diet. When offspring were 10 weeks of age, vascular injury was induced by polyethylene cuff placement around the femoral artery.

Results: Birth weight in offspring from dams fed LP until delivery (LPO) was significantly lower, but body weight was the same at 2 weeks after birth compared with that in NP offspring (NPO). Arterial blood pressure at 12 weeks of age did not differ between LPO and NPO. Neointima formation was exaggerated in LPO compared with NPO and associated with an increase in cell proliferation assessed by proliferating cell nuclear antigen (PCNA) staining index. Moreover, LPO showed enhanced expression of monocyte chemotactic protein-1, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and production of superoxide anion in the injured artery. Moreover, mRNA expression of isoforms of NAD(P)H oxidase subunits such as p22phox, p40phox, p47phox, p67phox, gp91phpx, and Rac1 in the injured arteries were enhanced in LPO. Furthermore, HIF-1α expression was increased in LPO compared with that in NPO.

Conclusions: These results suggest that maternal low-protein diet-induced FGR increases susceptibility of the vasculature to postnatal injury.

Keywords: blood pressure; cell proliferation; fetal growth restriction; hypertension; hypoxia; inflammation; oxidative stress; vascular remodeling..