Research Article: Inherited risk plus prenatal insult caused malignant dysfunction in mesenteric arteries in adolescent SHR offspring

Date Published: April 24, 2019

Publisher: Public Library of Science

Author(s): Yuan Zhong, Xueqin Feng, Ting Xu, Chunli Yang, Wenna Zhang, Xueyi Chen, Xiaorong Fan, Likui Lu, Meng Zhang, Lingjun Li, Zhice Xu, Michael Bader.

http://doi.org/10.1371/journal.pone.0215994

Abstract

Prenatal hypoxia can induce cardiovascular diseases in the offspring. This study determined whether and how prenatal hypoxia may cause malignant hypertension and impaired vascular functions in spontaneous hypertension rat (SHR) offspring at adolescent stage. Pregnant SHR were placed in a hypoxic chamber (11% O2) or normal environment (21% O2) from gestational day 6 until birth. Body weight and blood pressure (BP) of SHR offspring were measured every week from 5 weeks old. Mesenteric arteries were tested. Gestational hypoxia resulted in growth restriction during 6–12 weeks and a significant elevation in systolic pressure in adolescent offspring at 12 weeks old. Notably, endothelial vasodilatation of mesenteric arteries was impaired in SHR adolescent offspring exposed to prenatal hypoxia, vascular responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were reduced, as well as plasma nitric oxide levels and expression of endothelial nitric oxide synthase (eNOS) in vessels were decreased. Moreover, mesenteric arteries in SHR offspring following prenatal hypoxia showed enhanced constriction responses to phenylephrine (PE), associated with up-regulated activities of L-type calcium channel (Ca2+-dependent), RhoA/Rock pathway signaling (Ca2+-sensitization), and intracellular Ca2+ flow. Pressurized myograph demonstrated altered mechanical properties with aggravated stiffness in vessels, while histological analysis revealed vascular structural disorganization in prenatal hypoxia offspring. The results demonstrated that blood pressure and vascular function in young SHR offspring were affected by prenatal hypoxia, providing new information on development of hypertension in adolescent offspring with inherited hypertensive backgrounds.

Partial Text

Hypertension, affecting more than 25% of adult ≥30 years old globally [1], is also a great problem in children and adolescents [2–4]. It has been widely accepted that interaction of genetic and environmental factors is critical for development of hypertension [3]. Previous studies using inherited hypertensive models has revealed that adverse prenatal influences, including exposure to nicotine [4], malnutrition [5,6] and high salt diets [7] negatively impacted on cardiovascular systems in young offspring. However, it is unknown whether and how hypoxia during pregnancy may affect blood pressure at adolescent stage in the offspring with hypertension-related genetical defects. Answering this question would further increase our understanding how genetic and environmental interactions impacts on development of hypertension.

Data are expressed as mean ± SEM. Differences were considered significant at P < 0.05 by two-tailed unpaired Student’s t-test or two-way ANOVA followed by Bonferroni test, where appropriate. Statistical analysis was carried out with GraphPad Prism 5. Essential hypertension is the form of “hypertension” without identifiable cause as its definition, affecting more than 90% of hypertensive patients [26,27]. Usually appearance of hypertension is shown in patients in adult stages. It is well recognized that genetic and environmental interactions are basic hypothesis for development of essential hypertension. The major idea of the present study was to use a hypertension sensitive genetic model with special environmental treatments during critical early developmental period, to determine whether and how appearance of hypertension would move to younger ages. The results showed that the SHR offspring exposed to prenatal hypoxia exhibited greater risks in development of hypertension at adolescent age, as evidenced by enhanced resistance of small mesenteric arteries in early life periods. Importantly, the finding demonstrated that hypertension genetic model plus prenatal environmental insults such as hypoxia during pregnancy would make worse conditions and consequences for the vascular development, contributing to onset of essential hypertension in early life of the young offspring, proving that environmental factors during critical developmental periods play important roles in vascular dysfunction as well as hypertension in individuals with genetic defects.   Source: http://doi.org/10.1371/journal.pone.0215994

 

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