Loss‐ And Gain of Function Mutations in the Type 1 IP3 Receptor (IP3R1) Modify Agonist‐Evoked Vasoactive Responses in Cerebral and Skeletal Muscle Resistance Arteries From Adult Mice

Calcium mobilization within vascular smooth muscle and endothelial cells of small resistance arteries plays a critical role in agonist‐evoked vasoconstriction and dilation, respectively. Despite the recognized contribution of IP3‐mediated intracellular Ca 2+ release for agonist‐evoked vasoactive responses, it has been difficult to study this process acutely in native arteries, due to the lack of selective pharmacological agents or experimental strategies to target the predominant IP3R1. In humans, heterozygous mutations in the IP3R1 are known to produce either loss‐of‐function (LOF) or gain‐of‐function phenotypes for Ca 2+ release that impact cerebellar activity (e.g. ataxia), yet it remains unclear how these global mutations affect the cardiovascular system. To facilitate such investigation, we have engineered novel genetic knock‐in mice harbouring a single amino acid mutation at position Asp2594 in the transmembrane S6 helix of the endogenous IP3R1 Ca 2+ release channel that confers either a LOF (Asp2594Ala) or GOF (Asp2594Lys) phenotype, respectively. In permeabilized HEK293 cells expressing these mutant receptors, the LOF mutation shifted IP3‐mediated ER Ca 2+ release ~2‐fold to the right, whereas the GOF mutation produced a 2.3‐fold leftward shift compared with wild‐type (WT) IP3R1. In endothelium‐denuded cerebral arteries pressurized to 10 mmHg, the sensitivity of serotonin‐evoked vasoconstriction was reduced in vessels from heterozygous LOF mice compared with WT, whereas agonist responsiveness was enhanced in arteries from heterozygous GOF mice. Vasoconstriction in response to the thromboxane receptor agonist U46619 was modestly enhanced by the GOF mutation, but largely unaffected in arteries from LOF mice. In cannulated cremaster skeletal muscle arteries from LOF and GOF mice pressurized to 70 mmHg, the sensitivity of endothelium‐dependent, acetylcholine‐mediated inhibition of myogenic tone was right shifted (3.7‐fold) and left shifted (2‐fold), respectively, compared with vessels from WT. Comparable changes in functional sensitivity were observed in response to the endothelium‐dependent vasodilator bradykinin. In contrast, dilation evoked by the NO donor sodium nitroprusside was not different among the three genotypes. Collectively, these data demonstrate that genetic modification of IP3R1‐mediated Ca 2+ mobilization in small resistance arteries functionally impacts agonist‐evoked vasoactive responses. These observations highlight the importance of IP3R1 activity in the vascular wall, and further implicate vascular impairment as a contributing factor to the neurological dysfunction observed in patients with LOF and GOF IP3R1 mutations. Support or Funding Information This work was funded by the following research grants from the Canadian Institutes of Health Research: MOP‐97988 (WCC), MOP‐142467 (APB) and PJT‐155963 (WC, WCC and APB).

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