Placental 11 beta-hydroxysteroid dehydrogenase and the programming of hypertension.
Excessive foetal exposure to glucocorticoids retards growth and "programmes" adult hypertension in rats. Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which catalyses the conversion of corticosterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD, and enzyme activity correlates with birth weight. Moreover, inhibition of placental 11 beta-HSD in the rat reduces birth weight and produces hypertensive adult offspring, many months after prenatal treatment with enzyme inhibitors; these effects are dependent upon maternal adrenal products. These data suggest that placental 11 beta-HSD, by regulating foetal 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, deficiency 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, explain the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, purification and cDNA cloning of a distinct human placental 11 beta-HSD (type 2) will aid the further study of these intriguing findings.
University of Edinburgh, Department of Medicine, Western General Hospital, Edinburgh, U.K.
J R
JR
Seckl
R
R
Benediktsson
R S
RS
Lindsay
R W
RW
Brown
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D006973:Hypertension / Q000196:embryology / Q000201:enzymology / Q000209:etiology*; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007328:Insulin / Q000502:physiology; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy
D005938:Glucocorticoids; D006133:Growth Substances; D007328:Insulin; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases