Angiotensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spiral arteries in first-trimester decidua

OBJECTIVE: The angiotensinogen Thr235 polymorphism associated with preeclampsia is tightly linked to a mutation in the angiotensinogen promoter A(-6), which may lead to elevated expression in decidual spiral arteries. We hypothesize that locally elevated angiotensin II levels play a role in failed physiologic change leading to preeclampsia. Our objective was to determine whether spiral artery morphologic characteristics were different in first- trimester decidual samples from women homozygous for the angiotensinogen Thr235 allele and women homozygous for the normal angiotensinogen Met235 allele. STUDY DESIGN: We used quantitative histologic analysis to study 1266 spiral artery cross-sections in decidual samples obtained from normal pregnancies (n = 53) terminated at 8 weeks' gestation. To define vessel characteristics before pregnancy-induced remodeling, we also examined 60 arteries in nonpregnant endometrial control samples (n = 5). We measured the aspect ratio, media area, and external diameter of each cross-section with Image-Pro plus software. Maternal angiotensinogen genotypes were determined by means of mutagenically separated polymerase chain reaction. Average spiral artery morphologic measurements were compared between genotypes with the Student t test. RESULTS: The media area/external diameter ratio was lower in decidual samples than in endometrial samples (P < .0001), consistent with pregnancy-induced physiologic changes. Women homozygous for the angiotensinogen Thr235 allele (n = 11) had a greater area/diameter ratio than did women homozygous for the normal angiotensinogen Met235 allele (n = 11, P < .05). Samples from heterozygous women (n = 31) had intermediate values. CONCLUSION: Our results suggest that the angiotensinogen Thr235 allele predisposes women toward abnormal physiologic change, potentially beginning the cascade of events leading to preeclampsia.