Introduction. Sortillin-related VPS10P containing receptor (SorCS2) is expressed in neurons and other tissues during development where it mediates trafficking of target proteins between cell membrane and intracellular compartments. It has also been suggested that SorCS2 modulates signal transduction (Malik et al., 2020; Salasova et al., 2022). Moreover, SorCS2 is upregulated in the vascular wall under pathological conditions, e.g., atherosclerosis (Amadio et al., 2017). The aim of this study was to elucidate the contribution of endothelial and smooth muscle SorCS2 to the vascular function.

Method. We compared mesenteric small arteries (MSA) from endothelium- and smooth-muscle-specific knockouts (KO) for SorCS2 with matching controls in isometric myograph. For the endothelium-specific KO study, mice of two genotypes were used as controls: mice with floxed SorCS2 gene but without any Cre-recombinase expression, and mice with Cre-recombinase expression without any SorCS2-floxed gene. The endothelium-specific SorCS2 KO was constitutive KO with Cre expression controlled by Tie2 promoter. For this knockout, the mice were grouped into homozygote and heterozygote sub-groups, respectively. Cre expression was controlled by estrogen receptor type 2 under smooth-muscle-myosin-heavy-chain promoter and the smooth-muscle-specific knockout was induced by tamoxifen treatment. Vascular compliance, inner arterial diameters, noradrenaline-induced contraction, acetylcholine-induced relaxation, and relaxation to NO donor, sodium nitroprusside were compared between KOs and matching wild types.

Results. The MSA from endothelial-specific SorCS2 homozygote KO mice (n= 5-6) showed reduced compliance and reduced contractility to noradrenaline in comparison with the matching controls (n = 3-6). Furthermore, the MSA from endothelial-specific SorCS2 homozygote KO (n=5-6) demonstrated an increased sensitivity to acetylcholine-induced relaxation, which seemed to be NO-dependent. The MSA from smooth-muscle-specific SorCS2 KO (n = 3) had no changes in both acetylcholine- and sodium-nitroprusside-induced relaxations but showed decreased noradrenaline-induced contraction and compliance in comparison with the control arteries.

Conclusion. Our findings from the cell-specific vascular KO models indicate that SorCS2 contributes to endothelial- and smooth muscle-cell functions in murine mesenteric arteries.