PLACENTAL 11-BETA-HYDROXYSTEROID DEHYDROGENASE AND THE PROGRAMMING OFHYPERTENSION

Excessive foetal exposure to glucocorticoids retards growth and ''prog rammes'' adult hypertension in rats. Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which catalyses the conversion of cortico sterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans t here is considerable natural variation in placental 11 beta-HSD, and e nzyme activity correlates with birth weight. Moreover, inhibition of p lacental 11 beta-HSD in the rat reduces birth weight and produces hype rtensive adult offspring, many months after prenatal treatment with en zyme inhibitors; these effects are dependent upon maternal adrenal pro ducts. These data suggest that placental 11 beta-HSD, by regulating fo etal exposure to maternal glucocorticoids, crucially determines foeto- placental growth and the programming of hypertension. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD activity. Thus, deficien cy of the placental barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and foeto-placental programming of later disease. These data may, at least in part, explai n the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, puri fication and cDNA cloning of a distinct human placental 11 beta-HSD (t ype 2) will aid the further study of these intriguing findings.