Association of the calcitonin receptor-like receptor (CLR) with receptor-activity modifying proteins (RAMP)-1, -2 or -3 forms functional receptor complexes either for calcitonin gene-related peptide (CGRP, (CLR+RAMP-1)) or adrenomedullin (AM, (CLR+RAMP-2 or CLR+RAMP3)). CGRP, although poorly defined, might mediate in part the cerebral blood flow auto-regulation (CA) of in response to changes of the systemic blood pressure. AM might be even more important for the CA since the AM levels are about 50% higher in the cerebral circulation than in the peripheral vasculature because cerebral endothelial cells secrete large amounts of AM. Interestingly, even small variations in systemic blood pressure (+/­30 mmHg) result in rapid (within 6h) changes of mRNA levels of RAMP-2 but not of CLR in numerous brain structures. Here we tested the hypothesis that the chronic hypertension induced shift of the CA to higher blood pressures is at least partly due to a modification of the CLR/RAMP expression ratio in brain vessels. We found that in transgenic mice over-expressing the rat CLR under the control of a smooth muscle a-actin promoter the lower CA limit increased about 45% higher 8 weeks after hypertension induction using the one-kidney-one-clip model. In contrast in wild type littermates the same treatment resulted in a significantly higher shift of the lower CA limit of about 80%. We are currently investigating the number of AM and CGRP binding sites in the brains of the hypertensive mice using receptor autoradiography as well as the RAMP-1/RAMP-2 expression ratio using rtPCR. So far we conclude that increased CLR signaling could protect from the hypertension-induced shift of the lower CA limit.