Cardiovascular consequences of innate immune complement dysregulation

Activation of the innate immune complement system is important for normal pregnancy, but excessive activation is associated with hypertensive disorders of pregnancy such as preeclampsia. Reduced regulation of the complement system is also linked to adverse pregnancy outcomes, likely due to excessive complement activation. Preeclampsia affects both mother and child, with fetal growth restriction and increased risk for cardiometabolic and neurodevelopmental disorders developing in offspring. Previous studies of others have shown that mice deficient in the complement regulator CSMD3 (Cub and Sushi Multiple Domains 3) are growth restricted at birth and exhibit neurodevelopmental disorders similar to offspring of preeclamptic pregnancies. This suggests that the lack of CSMD3 may also increase the risk of adverse cardiovascular outcomes in the offspring. Thus, we hypothesized that CSMD3 knockout (-/+, -/-) mice would have vascular dysfunction and high blood pressure, similar to offspring of preeclamptic pregnancies. To test this hypothesis, we evaluated systolic blood pressure, as well as vasoconstriction and vasodilation of isolated mesenteric arteries from 7-14 week old female CSMD3 knockout mice compared to C57Bl/6J mice. After a 2 week acclimation period, mean systolic blood pressure measured by tail cuff plethysmography and averaged over an 8 day test period was significantly greater in female CSMD3 (-/-) mice compared to female C57Bl/6J mice (141 ± 2.6 mm Hg vs 129 ± 1.9 mm Hg, p< 0.05, n=4/group). Mesenteric arteries from C57Bl/6J and CSMD3 hetero (-/+) and homozygous (-/-) knockout mice were mounted in a wire myography system to measure vascular function in response to vasoconstrictors and vasodilators. In C57Bl/6J mice, sex differences in endothelial-dependent reactivity to acetylcholine were apparent with the maximal dilator response as well as slope of the concentration response curve being greater in female compared to male C57Bl/6J mice. Responsiveness of mesenteric arteries isolated from C57Bl/6J mice were then compared to hetero- and homozygous CSMD3 knockout mice (n=8-10/group) combined. Neither vasoconstriction in response to U46619, a thromboxane mimetic, nor vasodilation in response to the endothelial-independent dilator sodium nitroprusside were significantly different by strain. However, when hetero- and homozygous CSMD3 knockout mice combined were compared to C57Bl/6J mice, endothelial-dependent vasodilation in response to acetylcholine was impaired in female, but not male, mice. A significant decrease in the maximal dilator response as well as the slope of the concentration response curve (ANOVA sex strain effect, p< 0.05) was noted comparing female C57Bl/6J mice to female hetero- and homozygous CSMD3 knockout mice combined. Thus, these data suggest that impaired endothelial-dependent vasodilation in female CSMD3 knockout animals contributes to increased blood pressure. The similarities between offspring of hypertensive pregnancies and CSMD3 knockout mice suggests an increased risk of a preeclamptic phenotype during pregnancy in the absence of this complement regulator. Funded in part by Longer Life Foundation grant and Washington University ICTS grant (AJ) and Whiteside Institute for Clinical Research, a collaboration of St Lukes Hospital, Clinics and Foundation and the University of Minnesota Medical School Duluth Campus (JFR) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.