Pregnancy is associated with vascular adaptations involving vasodilation of the systemic vasculature and increased uterine artery blood flow. We and others reported that calcitonin gene-related peptide (CGRP) family peptides, CGRP and adrenomedullin (ADM), represents a novel second line of defense for regulating these pregnancy-induced vascular adaptations. In hypertensive pregnancy disorders such as pre-eclampsia(PE) these vascular adaptations are inadequate perhaps due to elevated levels of soluble fms-like tyrosine kinase (sFLT-1), increased angiotensin2 (ATII) sensitivity and vascular dysfunction involving nitric oxide system. Although our previous studies demonstrated a role for these peptides in a rat model, it is not known in women if this critically important peptide- receptor system is upregulated in maternal vasculature during normal pregnancy and whether failure of its pregnancy-related upregulation has clinical relevance in causing PE- associated vascular dysfunction, and whether this system could be targeted to reverse PE-associated vascular dysfunction. Four specific aims are proposed using human tissues and sFLT-1-induced mouse model of PE to test the central hypothesis that an intact and functional CGRP and ADM system during pregnancy would reduce the chances of developing the symptoms of preeclampsia. Specific aim 1: Determine if CGRP and ADM can reverse sFLT-1-induced hypertension and fetal growth restriction in sFLT-1 overexpressing mouse model of PE. We will assess effects of CGRP and ADM infusion on feto-placental weights, hypertension and elevated vascular sensitivity to ATII in sFLT-1 overexpressing mice. Specific aim 2: Assess if vascular relaxation responses and signaling mechanisms of CGRP and ADM are decreased in omental artery (OA) from women with PE compared to their gestation age-matched unaffected controls. We will determine if vascular relaxation sensitivity of OA for CGRP and ADM is reduced in PE compared to the unaffected pregnancy, and determine the mechanisms involved. Specific aim 3: Examine if CGRP and ADM can relax uterine arteries (UTA) in pregnant women and assess their mechanisms of action. We will assess if CGRP and ADM induced vascular relaxation effects are greater in UTA from pregnant compared to non- pregnant women, and identify mechanisms involved. Specific aim 4: Determine if sFLT-1 and ATII impair relaxation responses to CGRP and ADM and exert adverse effects on expression of CRLR and 3 RAMPs, and on association of CRLR with 3 RAMPs, and with CGRP and ADM in human vascular smooth muscle cells. In summary, this is the first systematic study assessing molecular and functional regulatory effects of CGRP and ADM in human vasculature during pregnancy and therapeutic potential of the CGRP pathway for PE.