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In this issue of Hypertension, Care AS., and colleagues (1) show promising data supporting resveratrol supplementation during gestational and post-gestational periods for the treatment of essential hypertension in the offspring. Administration of resveratrol to spontaneously hypertensive rat (SHR) dams prevented high blood pressure in both male and female SHR progeny. Their results have clinical relevance for they demonstrate a subjugation of genetically inherited high blood pressure.
Hypertension is a leading health problem worldwide. It has a high prevalence and is associated with increased morbidity and mortality for cardiovascular and renal disease. An estimated one-third of the adult US population is hypertensive and an equivalent percentage suffers from pre-hypertension. Individuals with pre-hypertension are at a particular risk of developing overt hypertension. Furthermore, the costs for treatments and hospitalization are exorbitant (2, 3). Primary or essential hypertension is the most common form of hypertension. It is typically a genetic, progressive disease with susceptibility increasing based on individual confounding factors/environment. In contrast to secondary hypertension, treatment of essential hypertension cannot be addressed by removing the known cause. While essential hypertension is treatable, it is not curable. Treatment goals focus on the prevention of the key consequences of elevated BP. Several effective antihypertensive drugs are available nowadays such as diuretics, angiotensin-converting enzyme (ACE) inhibitors/ angiotensin II receptor blockers, beta blockers, and calcium channel blockers. However, they require constant administration or recurrence may take place. For those reasons, a significant effort should be devoted to the discovery of a strategy for early prevention.
The SHR is a well known animal model of human essential hypertension. It was developed in the early 1960s by Okamoto and Aori by breeding Wistar-Kyoto rats with high blood pressure (4). Numerous studies have utilized SHRs to research treatment options. Currently available anti-hypertensive agents are effective in controlling hypertension in SHRs. However, since their hypertension is genetically inherited, treatment discontinuation results in the reappearance of high blood pressure.
Resveratrol, or 3,5,4'-trihydroxy-trans-stilbene, is a natural polyphenolic molecule naturally found in high concentrations in red grapes as well as in berries and peanuts. The cardioprotective effect of resveratrol was first observed in 1992. Since then, resveratrol supplementation has been considered as a potential therapeutic strategy for the treatment of cardiovascular diseases and other chronic health conditions. The cardioprotective effects of resveratrol are perhaps due to its potent anti-oxidant properties as well as it being a nitric oxide signaling pathway modulator. These characteristics make it an attractive target for the prevention and treatment of hypertension. Resveratrol has been studied in various animal models of hypertension and in limited human clinical trials (5).
In 2011, Bhatt and collaborators (6) administered resveratrol to SHR pups starting at weaning (3-4 weeks of age) for 10 weeks. BP was measured at the end of the experiment and resveratrol supplementation resulted in lower blood pressure (~ 20 mmHg). In another study (7), resveratrol administration to 10 week old SHRs for 5 weeks lowered SAP stating at 2 weeks after supplementation. However, treatment withdrawal resulted in an immediate restoration of hypertension. The ability of resveratrol to produce sustained, long-term reductions in arterial pressure remains controversial. Similarly to other anti-hypertensive drugs, resveratrol is considered to have an acute effect and requires continued administration in order to exhibit uninterrupted effects.
It is well established that blood pressure in later life can be programmed not only by genetic inheritance but also by the pre- and post-natal milieux. Studies using insults during pregnancy (i.e. preeclampsia, or nutritional restriction) in animal models result in persisting cardiovascular dysfunctions in later of life of the offspring despite their genetic background being normal (8). Similarly, post-natal exposure to stress by separating the offspring from the dams for a few hours a day also translated into enhanced susceptibility to high blood pressure in response to ANGII (9). These results suggest the environment plays a crucial role in the stemming phenotypes. Moreover, despite the genotype being programmed to become hypertensive, cross-fostering of SHR offspring to normotensive WKY (10) dams results in an intermediate phenotype as they exhibit lower blood pressure compared to non cross-fostered SHRs. Thus, the progression of high blood pressure in these animals is not strictly predetermined by genetic factors. Rather, a genetic predisposition to hypertension interacts with the pre-weaning environment to determine an animal’s cardiovascular phenotype in adulthood.
Care et al (1) successfully show that resveratrol administration to the dams, not the pups, during pregnancy and nursing prevents the phenotypic expression of high blood pressure in the SHR offspring. The peculiarity of this study lies in the lowering of blood pressure in the SHR model past adulthood, overcoming genetic programming. In contrast to the aforementioned studies (6, 7) in which resveratrol was given directly to SHR animals to lower their blood pressure, it appears gestational + postnatal intervention is much more effective since the discontinuation of treatment did not reverse the phenotype. The mechanism is likely due to a re-set of the vascular responsiveness and NO bioavailability of the offspring (1), but how? Neither blood flow patters from the mother to fetus nor prolactin concentration in the milk is involved (1). Resveratrol may acutely lower the blood pressure of the dams leading to a less adverse fetal environment to the fetus and modulating the differential turning on and off of genes. Further studies are required to identify how maternal physiology, milk composition, and rearing behavior during resveratrol supplementation lead to the re-setting of the offspring phenotype.
In summary, this study by Care et al (1) provides extensive evidence that timing of resveratrol treatment is crucial to preventing hypertension. Nevertheless, there are still many unknowns; for example, safety, dosage, and mechanism. Studies focused not only on the pups but also the dams could advance our knowledge on the effects of pre- and post-natal resveratrol supplementation in the overcoming of genetic programming in populations at risk of developing essential hypertension.
Sources of Funding
The research of the author is supported by NIH P20GM104357 grant and AHA 16SDG27770041 grant