Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness

Several examples of functional G-protein-coupled receptor heterodimers have been identified. However, it is not known whether receptor heterodimerizat ion is involved in the pathogenesis of human disorders. Here we show that i n preeclamptic hypertensive women, a significant increase in heterodimeriza tion occurs between the AT(1)-receptor for the vasopressor angiotensin II a nd the B-2-receptor for the vasodepressor bradykinin. AT(1)-B-2-receptor he terodimerization in preeclampsia correlated with a 4-5-fold increase in B-2 -receptor protein levels. Expression of the AT(1)-B-2 heterodimer increased the responsiveness to angiotensin II and conferred resistance in AT(1)-rec eptors to inactivation by reactive oxygen species raised in normotensive an d preeclamptic pregnancies. We suggest that AT(1)-B-2 heterodimers contribu te to angiotensin II hypersensitivity in preeclampsia. Moreover, we identif y preeclampsia as the first disorder associated with altered G-protein-coup led receptor heterodimerization.