Placental Insufficiency Leads to Developmental Hypertension and Mesenteric Artery Dysfunction in Two Generations of Sprague-Dawley Rat Offspring1

Abstract

It is generally accepted that preeclampsia results from reduction in perfusion to the uteroplacental unit leading to maternal hypertension and fetal growth restriction. Placental insufficiency creates an environment of fetal undernutriton, predisposing the fetus to the development of adult disease. In this study, we characterized the development and perpetuation of hypertension in two generations of male and female offspring subjected to an environment of fetal undernutrition via reduced uteroplacental perfusion pressure. Further, we examined vascular responses of resistance arteries in these animals to determine the influence of placental insufficiency on the development and perpetuation of hypertension. Experimental dams underwent a surgical procedure to reduce uteroplacental perfusion pressure, with resulting offspring comprising the first generation (F1). One male and one female from each of the F1 experimental litters served as breeders of the second generation (F2). Weekly systolic blood pressure measurements were obtained from 4 to 24 wk in control, F1, and F2 offspring. Vascular responsiveness to the vasoconstrictors phenylephrine and potassium chloride and the vasorelaxants acetylcholine and sodium nitroprusside was determined in the three offspring groups at 6, 9, and 12 wk of age. Our findings indicate that placental insufficiency during a critical developmental window in late gestation leads to hypertension in juvenile Sprague-Dawley rat offspring and is perpetuated in a second generation of offspring in a gender-specific manner. Further, exposure to placental insufficiency during late gestation leads to developmental alterations characterized by vascular hyperresponsiveness, perpetuated to a second generation of offspring in the absence of persistent environmental stimuli, contributing to hypertension.

Uteroplacental Insufficiency and Lactational Environment Separately Influence Arterial Stiffness and Vascular Function in Adult Male Rats

“…10 Experimental models of uteroplacental insufficiency where uterine perfusion is reduced during the last third of pregnancy in rats yield growth restricted offspring (Ϸ10%) that develop hypertension, and there is increasing evidence for altered vascular function. 11,12 The early postnatal environment has also been identified as a critical period, such that rapid childhood growth in infants born small or thin is associated with endothelial dysfunction 13 and heightened cardiovascular risk. 14,15 The early lactational environment may also influence cardiovascular risk.…”

Developmental Programming of Hypertension

“…Sex differences in adult blood pressure are not observed in models of undernutrition programmed by placental insufficiency in the rat when assessed indirectly by the tail cuff in conscious, restrained animals. 11,48 Conversely, sex differences in adult blood pressure are observed when measured directly by telemetry 49,50 ; blood pressure after puberty is stabilized to normotensive levels in female IUGR, yet is further increased in male IUGR. 49,50 Castration abolishes hypertension in male IUGR 49 ; ovariectomy induces hypertension in female IUGR rats, an effect reverted by hormonal replacement therapy.…”

Epigenetic regulation during mammalian oogenesis

“…In this light, embryo culture has been shown to alter placental morphology and function (Sjoblom et al 2005). In addition, placental insufficiencies adversely affect fetal development, including the on-set of adult disease (Anderson et al 2006;Hayashi and Dorko 1988). Early alterations in gene expression, particularly of imprinted genes may be a key driving force in perturbing placental development and function, resulting in altered fetal development, and may impact blastomere fate allocation during earlier development.…”