{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:09:47Z","timestamp":1784200187531,"version":"3.55.0"},"reference-count":104,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Center for Cardiovascular Research","award":["FKZ 81Z1710101 and FKZ 81Z0710102"],"award-info":[{"award-number":["FKZ 81Z1710101 and FKZ 81Z0710102"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LU 1490\/3-2 and 335549539\/GRK 2381"],"award-info":[{"award-number":["LU 1490\/3-2 and 335549539\/GRK 2381"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3\u2032,5\u2032-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO\/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2\u03b1. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC\/cGMP\/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC\/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents.<\/jats:p>","DOI":"10.3390\/ijms22189925","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T21:47:21Z","timestamp":1631656041000},"page":"9925","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cyclic GMP-Dependent Regulation of Vascular Tone and Blood Pressure Involves Cysteine-Rich LIM-Only Protein 4 (CRP4)"],"prefix":"10.3390","volume":"22","author":[{"given":"Natalie","family":"L\u00e4ngst","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Adler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Schweigert","sequence":"additional","affiliation":[{"name":"Cardiovascular Systems Medicine and Molecular Translation, University Center of Cardiovascular Science, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"},{"name":"DZHK, German Center for Cardiovascular Research, Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Kleusberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Cruz Santos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Knauer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Sausbier","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Zeller","sequence":"additional","affiliation":[{"name":"Cardiovascular Systems Medicine and Molecular Translation, University Center of Cardiovascular Science, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"},{"name":"DZHK, German Center for Cardiovascular Research, Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ruth","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lukowski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/wdev.91","article-title":"Understanding Vascular Development","volume":"2","author":"Udan","year":"2013","journal-title":"Wiley Interdiscip. 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