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These peptides signal through CLR\/RAMP1, 2, and 3 receptors, and protect against endothelial dysfunction in disease models. As such, CLR\/RAMP receptor agonists are considered important therapeutic candidates for various diseases. Methods and Results: Based on the screening of a series of palmitoylated chimeric ADM\/ADM2 analogs, we demonstrated a combination of lipidation and accommodating motifs at the hinge region of select peptides is important for gaining an enhanced receptor-activation activity and improved stimulatory effects on the proliferation and survival of human lymphatic endothelial cells when compared to wild-type peptides. In addition, by serendipity, we found that select palmitoylated analogs self-assemble to form liquid gels, and subcutaneous administration of an analog gel led to the sustained presence of the peptide in the circulation for &gt;2 days. Consistently, subcutaneous injection of the analog gel significantly reduced the blood pressure in SHR rats and increased vasodilation in the hindlimbs of adult rats for days. Conclusions: Together, these data suggest gel-forming adrenomedullin analogs may represent promising candidates for the treatment of various life-threatening endothelial dysfunction-associated diseases such as treatment-resistant hypertension and preeclampsia, which are in urgent need of an effective drug.<\/jats:p>","DOI":"10.3390\/ijms232113408","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T03:53:07Z","timestamp":1667447587000},"page":"13408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Sustained Activation of CLR\/RAMP Receptors by Gel-Forming Agonists"],"prefix":"10.3390","volume":"23","author":[{"given":"Chia Lin","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan 20878, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheqing","family":"Cai","sequence":"additional","affiliation":[{"name":"CL Laboratory LLC, Gaithersburg, MD 20878, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6690-9864","authenticated-orcid":false,"given":"Sheau Yu Teddy","family":"Hsu","sequence":"additional","affiliation":[{"name":"Adepthera LLC, San Jose, CA 95138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/30666","article-title":"RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor","volume":"393","author":"McLatchie","year":"1998","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S0014-5793(98)01587-7","article-title":"Receptor activity modifying proteins regulate the activity of a calcitonin gene-related peptide receptor in rabbit aortic endothelial cells","volume":"441","author":"Muff","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7264","DOI":"10.1074\/jbc.M305332200","article-title":"Intermedin is a calcitonin\/CGRP family peptide acting through the CRLR\/RAMP receptor complexes","volume":"279","author":"Roh","year":"2004","journal-title":"J. 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