Death‐associated protein kinase 3 regulates the myogenic reactivity of cerebral arteries

Autor: Sara R. Turner, Abdulhameed Al‐Ghabkari, David A. Carlson, Mona Chappellaz, Cindy Sutherland, Timothy A. J. Haystead, William C. Cole, Justin A. MacDonald
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Experimental Physiology, Vol 108, Iss 7, Pp 986-997 (2023)
Druh dokumentu: article
ISSN: 1469-445X
0958-0670
DOI: 10.1113/EP090631
Popis: Abstract The vascular smooth muscle (VSM) of resistance blood vessels is a target of intrinsic autoregulatory responses to increased intraluminal pressure, the myogenic response. In the brain, the myogenic reactivity of cerebral arteries is critical to homeostatic blood flow regulation. Here we provide the first evidence to link the death‐associated protein kinase 3 (DAPK3) to the myogenic response of rat and human cerebral arteries. DAPK3 is a Ser/Thr kinase involved in Ca2+‐sensitization mechanisms of smooth muscle contraction. Ex vivo administration of a specific DAPK3 inhibitor (i.e., HS38) could attenuate vessel constrictions invoked by serotonin as well as intraluminal pressure elevation. The HS38‐dependent dilatation was not associated with any change in myosin light chain (LC20) phosphorylation. The results suggest that DAPK3 does not regulate Ca2+ sensitization pathways during the myogenic response of cerebral vessels but rather operates to control the actin cytoskeleton. A slow return of myogenic tone was observed during the sustained ex vivo exposure of cerebral arteries to HS38. Recovery of tone was associated with greater LC20 phosphorylation that suggests intrinsic signalling compensation in response to attenuation of DAPK3 activity. Additional experiments with VSM cells revealed HS38‐ and siDAPK‐dependent effects on the actin cytoskeleton and focal adhesion kinase phosphorylation status. The translational importance of DAPK3 to the human cerebral vasculature was noted, with robust expression of the protein kinase and significant HS38‐dependent attenuation of myogenic reactivity found for human pial vessels.
Databáze: Directory of Open Access Journals
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