Functional Bias of Contractile Control in Mouse Resistance Arteries

Objective: Constrictor agonists set arterial tone through two coupling processes, one tied to (electromechanical), the other independent (pharmacomechanical) of membrane potential (VM). Their existence raises an intriguing query- are they variably engaged such that agonists elicit a range of vasomotor signatures, functionally biased to one mechanism or the other. This question underlies this study and our examination of constriction in mouse mesenteric arteries. Methods: Mouse mesenteric arteries were exposed to a classic Gq/11 (phenylephrine) or Gq/11/G12/13 (U46619) coupled receptor agonist, and responses monitored in the absence and presence of L-type Ca2+ channel/protein kinase inhibitors. This contractile work was supplement with measures of protein phosphorylation, VM and cytosolic Ca2+; conceptual insights were also garnered from computational modeling. Results: Each agonist elicited a constrictor response curve that was attenuated and rightward shifted by nifedipine, a finding consistent with functional bias; electromechanical coupling precedes pharmacomechanical, the latter's importance rising with concentration. Ensuing contractile and phosphorylation measures (CPI-17 & MYPT1 (T-855 & T-697)) revealed phenylephrine induced pharmacomechanical coupling through protein kinase C (PKC), whereas that of U46619 was tied to PKC and Rho-kinase. Additional work revealed a switch to complete pharmacomechanical coupling dominance when agonist superfusion was replaced with discrete application to a portion of artery. This switch was predicted by electromechanical modeling and aligns with measures of VM and cytosolic Ca2+. Conclusion: Our work illustrates that constrictors elicit functionally biased responses and that arteries toggle among contractile mechanisms, dependent on receptor signal bias, structural/electrical properties and how agents are applied. We discuss how hemodynamic control is intimately tied to functional bias in both health and disease states, including but not limited to arterial vasospasm. ### Competing Interest Statement The authors have declared no competing interest.