{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:38:48Z","timestamp":1789475928504,"version":"build-2803163510"},"reference-count":78,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RO1NS19971"],"award-info":[{"award-number":["RO1NS19971"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","award":["Grant\u2010In\u2010Aid"],"award-info":[{"award-number":["Grant\u2010In\u2010Aid"]}],"id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"\n Abstract<\/jats:title>\n \n Constrictor stimuli set arterial tone through coupling processes dependent (electromechanical) and independent (pharmacomechanical) of\n V<\/jats:italic>\n M<\/jats:sub>\n . As the latter receives limited attention, we conducted a focused examination of the cerebral circulation to identify key signalling kinases involved in tone development and their role in regulating blood flow. A multiscale approach was implemented extending from cells to live brain and including myography, western blotting, immunolabelling, two\u2010photon microscopy and modelling. We began by superfusing a G protein\u2010coupled receptor agonist (U46619) onto isolated mouse cerebral arteries to drive a concentration\u2010dependent constriction. Using pharmacology to separate the two processes, electromechanical coupling notably preceded pharmacomechanical, the latter tied to protein kinase C (PKC) activation. PKC\u03b4 mediated the pharmacomechanical response, irrespective of whether the agonist was superfused or discretely applied to elicit focal non\u2010electrical constriction. Further analysis revealed (1) the translocation of PKC\u03b4 to the membrane, indicating its activation, and (2) the identification of C\u2010kinase\u2010activated protein phosphatase\u20101 inhibitor of 17\u00a0kDa (CPI\u201017) and heat shock protein 27 (HSP27) as downstream phosphorylation targets of PKC\u03b4 involved in regulating tone. Focal non\u2010electrical constriction was observed\n in vivo<\/jats:italic>\n along penetrating arterioles, responses dependent on PKC\u03b4. Key findings were confirmed in human cerebral arteries, and modelling demonstrated how focal, non\u2010electrical control sets cerebral blood flow distribution. We conclude\u00a0pharmacomechanical coupling is robust in cerebral arteries and enabled by PKC\u03b4 through phosphorylation of CPI\u201017 and HSP27. This process allows arteries to focally constrict and presumptively optimize blood flow distribution when discrete stimuli are produced. We discuss how aberrant pharmacomechanical control could underlie focal vascular pathobiology and if PKC\u03b4 could be a target for therapeutic control.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Constrictors set arterial tone through coupling processes dependent (electromechanical) and independent (pharmacomechanical) of membrane potential.<\/jats:p>\n <\/jats:list-item>\n \n The relative contribution of electro\u2010 and pharmacomechanical coupling to cerebral arterial tone depends to the concentration and area to which constrictors are applied.<\/jats:p>\n <\/jats:list-item>\n \n Protein kinase C\u03b4 is a key transduction protein within pharmacomechanical coupling that enables a focal segment of cerebral artery to constrict independently of the lengthier vessel.<\/jats:p>\n <\/jats:list-item>\n \n Focal constriction is observed in live cerebral microcirculation and it helps set proper blood flow distribution within the brain.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289379","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T06:05:09Z","timestamp":1783404309000},"page":"6324-6347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protein kinase C\u03b4 and pharmacomechanical coupling: Re\u2010envisioning cerebral vascular control"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6495-2918","authenticated-orcid":false,"given":"Nadia","family":"Haghbin","sequence":"first","affiliation":[{"name":"Department of Physiology & Pharmacology, Robarts Research Institute, Schulich School of Medicine University of Western Ontario London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle S. 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