Sustained Activation of CLR/RAMP Receptors by Gel-Forming Agonists

Chang, Chia‐Lin; Cai, Zheqing; Hsu, Sze-Bi

doi:10.3390/ijms232113408

Cited by 5 publications

(5 citation statements)

References 157 publications

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“…Finally, it is important to mention that ADE101 has the ability to self-assemble into a liquid gel, as we have recently reported [176]. This gel formation enables the slow release of ADE101 (equivalent to Analog C-6 in reference [176]) in vivo . In rats, subcutaneous injection of the ADE101 gel solution resulted in sustained blood pressure reduction for more than two days in SHR rats, and increased dermal blood flow for over three days in Sprague Dawley rats.…”

Section: Discussionmentioning

confidence: 77%

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Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Chang

Cai²,

Hsu³

2023

Journal of Hypertension

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Objective(s):Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal–fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditionsMethods:To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14Results:The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.Conclusions:These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 77%

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Chang

Cai²,

Hsu³

2023

Journal of Hypertension

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“…It underestimated the level of ADE651 when compared to wild-type ADM2; therefore, future development of a more sensitive assay or protocol to estimate the ADE651 level is needed to precisely characterize the pharmacokinetics of antagonist gels in animals and humans. Moreover, in addition to the identification of gel-forming peptide antagonists described here, we have recently reported the identification of gel-forming peptide agonists for CLR/RAMP receptors ( Chang et al 2022 ). In that study, we showed that administration of gel-forming agonists results in a sustained increase of dermal blood flow in rats, and the gel formulation allows a localized stimulatory effect.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the screening of a series of chimeric ADM/adrenomedullin 2 (ADM2) peptides, we have recently identified a group of potent peptide CLR/RAMP receptor agonists ( Chang et al 2022 ), and peptide antagonists that potently inhibit CLR/RAMP1 and/or 2 signaling ( Chang and Hsu, 2019 ). By serendipity, we have also found that select antagonists such as ADE651 and ADE609 are capable of self-assembling into hydrogels in situ at low concentrations.…”

Section: Introductionmentioning

confidence: 99%

Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation

Chang

Cai²,

Hsu³

2022

Front. Pharmacol.

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Migraine affects ∼15% of the adult population, and the standard treatment includes the use of triptans, ergotamines, and analgesics. Recently, CGRP and its receptor, the CLR/RAMP1 receptor complex, have been targeted for migraine treatment due to their critical roles in mediating migraine headaches. The effort has led to the approval of several anti-CGRP antibodies for chronic migraine treatment. However, many patients still suffer continuous struggles with migraine, perhaps due to the limited ability of anti-CGRP therapeutics to fully reduce CGRP levels or reach target cells. An alternative anti-CGRP strategy may help address the medical need of patients who do not respond to existing therapeutics. By serendipity, we have recently found that several chimeric adrenomedullin/adrenomedullin 2 peptides are potent CLR/RAMP receptor antagonists and self-assemble to form liquid gels. Among these analogs, the ADE651 analog, which potently inhibits CLR/RAMP1 receptor signaling, forms gels at a 6–20% level. Screening of ADE651 variants indicated that residues at the junctional region of this chimeric peptide are important for gaining the gel-forming capability. Gel-formation significantly slowed the passage of ADE651 molecules through Centricon filters. Consistently, subcutaneous injection of ADE651 gel in rats led to the sustained presence of ADE651 in circulation for >1 week. In addition, analysis of vascular blood flow in rat hindlimbs showed ADE651 significantly reduces CGRP-induced vasodilation. Because gel-forming antagonists could have direct and sustained access to target cells, ADE651 and related antagonists for CLR/RAMP receptors may represent promising candidates for targeting CGRP- and/or adrenomedullin-mediated headaches in migraine patients.

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“…In their later studies, the researchers could evoke a sustained activation of CLR/RAMP1 and CLR/RAMP2 receptor signaling pathways using palmitoylated AM and AM2/intermedin analogues. 182 Moreover, the selected AM analogue was demonstrated to have gel-like characteristics, limiting its spatial spreading. Therefore, application of these gel-forming AM analogues would also provide a predominantly local stimulation of AM signaling pathways.…”

Section: Improving Pharmacologic Abilities Of Am By Peptide Modificat...mentioning

confidence: 99%

Clinical Potential of Adrenomedullin Signaling in the Cardiovascular System

Bálint

Nelson-Maney

Tian

et al. 2023

Circulation Research

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Numerous clinical studies have revealed the utility of circulating AM (adrenomedullin) or MR-proAM (mid-regional proAM 45-92) as an effective prognostic and diagnostic biomarker for a variety of cardiovascular-related pathophysiologies. Thus, there is strong supporting evidence encouraging the exploration of the AM-CLR (calcitonin receptor-like receptor) signaling pathway as a therapeutic target. This is further bolstered because several drugs targeting the shared CGRP (calcitonin gene-related peptide)-CLR pathway are already Food and Drug Administration-approved and on the market for the treatment of migraine. In this review, we summarize the AM-CLR signaling pathway and its modulatory mechanisms and provide an overview of the current understanding of the physiological and pathological roles of AM-CLR signaling and the yet untapped potentials of AM as a biomarker or therapeutic target in cardiac and vascular diseases and provide an outlook on the recently emerged strategies that may provide further boost to the possible clinical applications of AM signaling.

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Sustained Activation of CLR/RAMP Receptors by Gel-Forming Agonists

Cited by 5 publications

References 157 publications

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation

Clinical Potential of Adrenomedullin Signaling in the Cardiovascular System

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