Sex Steroid Hormones and Calcitonin Gene-Related Peptide

妊娠与血管适应有关，包括全身血管系统的血管舒张， 子宫动脉血流量增加。我们和其他人报道了降钙素基因相关肽（CGRP）家族 肽，CGRP和肾上腺髓质素（ADM），代表了一种新的第二道防线，调节这些 妊娠引起的血管适应在妊娠高血压疾病，如先兆子痫（PE） 这些血管适应性不足可能是由于可溶性FMS样酪氨酸激酶水平升高 （sFLT-1）、增加的血管紧张素2（ATII）敏感性和涉及一氧化氮系统的血管功能障碍。 虽然我们以前的研究证明了这些肽在大鼠模型中的作用，但在女性中还不清楚 如果这种至关重要的肽-受体系统在母体血管系统中在正常发育过程中上调， 妊娠及其妊娠相关上调失败是否与导致PE的临床相关性有关， 相关的血管功能障碍，以及该系统是否可以靶向逆转PE相关的血管功能障碍。 功能障碍使用人组织和sFLT-1诱导的小鼠PE模型提出了四个具体目标， 测试中心假设，一个完整的和功能性的CGRP和ADM系统在怀孕期间， 减少先兆子痫症状的发生。具体目标1：确定CGRP是否 ADM可逆转sFLT-1过表达的胎儿生长受限和sFLT-1诱导的高血压 小鼠PE模型。我们将评估CGRP和ADM输注对胎儿胎盘重量的影响， 高血压和血管对ATII的敏感性升高。具体目标2：评估 如果大网膜血管舒张反应和CGRP和ADM的信号传导机制降低， 动脉（OA）与PE女性相比，其妊娠年龄匹配的未受影响的对照。我们将 确定PE中OA对CGRP和ADM的血管舒张敏感性是否低于 未受影响的妊娠，并确定相关机制。具体目标3：检查CGRP和ADM 可以放松孕妇的子宫动脉（UTA），并评估其作用机制。我们将评估，如果 CGRP和ADM诱导的血管舒张作用在妊娠UTA中比非妊娠UTA中更大。 孕妇，并查明所涉机制。具体目标4：确定sFLT-1和ATII是否损害 对CGRP和ADM的舒张反应，并对CRLR和3种RAMPs的表达产生不利影响， CRLR与3种RAMPs、CGRP和ADM在人血管平滑肌细胞中的相关性。 总之，这是第一个评估CGRP分子和功能调节作用的系统研究 和ADM在妊娠期间人血管系统中的作用以及CGRP途径对PE的治疗潜力。

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.