Angiotensin II receptor blockade during gestation attenuates collagen formation in the developing rat heart

Objective: Fetal cardiac development includes rapid formation of a three-di mensional collagen network, composed mainly of type I and III fibrillar col lagens. Collagen fibrils have been found in cardiac jelly at very early sta ges of cardiac development and an thought to have structural and functional properties. In adult rat cardiac tissue, angiotensin ii (AngII) via AT1 re ceptor binding and AngII-regulated expression of transforming growth factor beta-1 (TGF-beta(1)) each upregulate collagen transcription. AT1 and AT2 r eceptor subtypes an developmentally regulated; both have been localized in fetal tissue where the AT2 receptor is considered a determinant of morphoge nesis. We sought to determine whether blockade of either receptor would res ult in attenuation of collagen mRNA expression and fibrillar collagen accum ulation and alter TGF-beta(1) mRNA expression in the developing fetal heart examined at birth. Methods: Pregnant rats were treated either with an AT1 receptor antagonist losartan or an AT2 receptor antagonist PD123319 and com pared with untreated age-matched controls. Offspring were studied within 24 h of birth. Type I and type III collagen mRNA expression, as well as TGF-b eta(1) mRNA expression, were examined by in situ hybridization. Collagen co ncentration was determined spectrophotometrically by picrosirius red staini ng and type I and III collagens were detected by immunoblotting. Results: W e found: (1) comparable birth weights in control and PD123319-rreated anima ls, but reduced body weighs in newborn losartan-treated animals; (2) compar ed to untreated animals, type I collagen and TGF-beta(1) mRNA expression in cardiac tissue were each equally reduced in both losartan and PD123319-tre ated animals; (3) increased type III collagen mRNA expression in both PD123 319- and losartan-treated groups; and (4) a significant decrease in total s oluble cardiac collagen concentration in both losartan and PD123319-treated groups, confirmed by attenuated immunoreactivity of type I and III collage ns in whole heart extracts by Western blotting. Conclusions: The results of these pharmacologic interventions suggest AngII receptors are expressed in cardiac tissue during gestation, where both AT1 and AT2 receptors are invo lved in the regulation of type I and III. collagen expression and structura l protein accumulation. These effects appear to be mediated, in part, by at tenuated cardiac TGF-beta(1) levels. The marked decrease in newborn cardiac collagen content has yet undefined functional consequences. (C) 1999 Elsev ier Science B.V. All rights reserved.