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Sex Steroid Hormones and Calcitonin Gene-Related Peptide

性类固醇激素和降钙素基因相关肽

基本信息

批准号：
10429906
负责人：
Madhu Lata S. Chauhan
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-20 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10429906
关键词：
Adverse effects Arteries Biological Blood Vessels Blood Volume Blood flow Calcitonin Gene-Related Peptide Cessation of life Clinical Competence Congestive Heart Failure Cyclic AMP Data Development Disease Failure Family Fetal Growth Fetal Growth Retardation Gestational Age Gonadal Steroid Hormones Human Hypertension Impairment Infusion procedures Investigation Ligands Maternal Mortality Medical Modeling Molecular Morbidity - disease rate Mus NG-Nitroarginine Methyl Ester Nitric Oxide Pathway interactions Patients Peptide Receptor Peptides Placentation Pre-Eclampsia Pregnancy Pregnant Women Protein Family Proteins Rattus Relaxation Reporting Role Signal Transduction Smooth Muscle Myocytes Solid Symptoms System Testing Therapeutic Up-Regulation Uteroplacental Circulation Uterus Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Smooth Muscle Vasodilation Weight Woman adrenomedullin base clinically relevant human tissue hypertensive mortality mouse model novel overexpression pregnancy disorder pregnant response

项目摘要

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.

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。功能障碍使用人体组织和sFLT-1诱导的PE小鼠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。

项目成果

期刊论文数量（105）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immunohistochemical localization of constitutive and inducible cyclo-oxygenases in rat uterus during the oestrous cycle and pregnancy.

发情周期和妊娠期间大鼠子宫中组成型和诱导型环氧合酶的免疫组织化学定位。

DOI：
10.1023/a:1003228427487
发表时间：
1998
期刊：
The Histochemical journal
影响因子：
0
作者：
Fang,L;Chatterjee,S;Dong,YL;Gangula,PR;Yallampalli,C
通讯作者：
Yallampalli,C

Gestational changes in calcitonin gene-related peptide, nerve growth factor, and its receptors in rat dorsal root ganglia.

妊娠期大鼠背根神经节降钙素基因相关肽、神经生长因子及其受体的变化。

DOI：
10.1095/biolreprod65.5.1601
发表时间：
2001
期刊：
Biology of reproduction
影响因子：
3.6
作者：
Lanlua,P;Gangula,PR;Taglialatela,G;Yallampalli,C
通讯作者：
Yallampalli,C

Effects of steroid hormones on calcitonin gene-related peptide receptors in cultured human myometrium.

类固醇激素对培养的人子宫肌层中降钙素基因相关肽受体的影响。

DOI：
10.1067/mob.2003.42
发表时间：
2003
期刊：
American journal of obstetrics and gynecology
影响因子：
9.8
作者：
Dong,Yuan-Lin;Wimalawansa,Suril;Yallampalli,Chandrasekhar
通讯作者：
Yallampalli,Chandrasekhar

Impact of Adrenomedullin on Mitochondrial Respiratory Capacity in Human Adipocyte.

肾上腺髓质素对人脂肪细胞线粒体呼吸能力的影响。

DOI：
10.21203/rs.3.rs-2600140/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Dong,Yuanlin;Vipin,VidyadharanAlukkal;Blesson,ChellakkanSelvanesan;Yallampalli,Chandrasekhar
通讯作者：
Yallampalli,Chandrasekhar

Enhanced mesenteric arterial responsiveness to angiotensin II is androgen receptor-dependent in prenatally protein-restricted adult female rat offspring.

在产前蛋白质限制的成年雌性大鼠后代中，肠系膜动脉对血管紧张素 II 的反应性增强是雄激素受体依赖性的。