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Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse
Nicole Morel1, Greet Vandenberg, Ali K Ahrabi
1Laboratoire de Physiologie Cellulaire, Université Catholique de Louvain, Avenue Hippocrate 55, UCL 5540, Brussels, Belgium. nicole.morel@uclouvain.be
Insights
Polycystic kidney disease (PKD) gene Pkd1 haploinsufficiency in mice leads to elevated blood pressure and altered vascular function. These Pkd1+/- mice show impaired calcium signaling in aorta, impacting cardiovascular health.
Area of Science:
- Cardiovascular Biology
- Nephrology
- Molecular Biology
Background:
- Mutations in the PKD1 gene are a primary cause of autosomal dominant polycystic kidney disease (ADPKD).
- ADPKD is frequently associated with significant cardiovascular complications, including hypertension and vascular dysfunction.
- The precise mechanisms linking PKD1 mutations to vascular pathology remain incompletely understood.
Purpose of the Study:
- To investigate whether heterozygous Pkd1 deficiency (Pkd1+/-) in mice results in a vascular phenotype.
- To assess age-dependent changes in vascular function and blood pressure in Pkd1 haploinsufficient mice.
- To explore the role of intracellular calcium homeostasis in the vascular alterations associated with Pkd1 haploinsufficiency.
Main Methods:
- Utilized Pkd1+/- mice and wild-type (Pkd1+/+) littermates for comparative analysis across different age groups.
- Measured systolic blood pressure using tail-cuff methods and telemetric recordings in conscious, unrestrained animals.
- Assessed vascular contractility and relaxation responses in isolated aortic segments.
- Quantified intracellular calcium levels and analyzed mRNA expression of key calcium-handling proteins in aortic tissues.
Main Results:
- Systolic blood pressure was significantly elevated in 30-week-old Pkd1+/- mice compared to controls, while telemetric recordings showed no difference.
- Abdominal aortas from older Pkd1+/- mice exhibited increased contractile responses and impaired relaxation.
- Alterations in intracellular calcium signaling were observed, including reduced basal and evoked calcium levels and increased calcium release.
- Significant changes in the mRNA expression of Pkd2, Trpc1, Orai1, and Serca2a were detected in Pkd1+/- aortas.
Conclusions:
- Pkd1 haploinsufficiency is associated with the development of hypertension and vascular dysfunction in a mouse model.
- Altered intracellular calcium homeostasis and compensatory changes in calcium signaling proteins contribute to vascular abnormalities in Pkd1+/- mice.
- These findings highlight a direct link between Pkd1 deficiency and cardiovascular complications, offering insights into ADPKD pathogenesis.
Abstract:
Mutations in PKD1 are associated with autosomal dominant polycystic kidney disease (ADPKD), which leads to major cardiovascular complications. We used mice with a heterozygous deletion of Pkd1 (Pkd1+/-) and wild-type (Pkd1+/+) littermates to test whether Pkd1 haploinsufficiency is associated with a vascular phenotype in different age groups. Systolic blood pressure measured by the tail-cuff method was similar up to 20 weeks of age, but significantly higher in 30-week-old Pkd1+/- compared to Pkd1+/+. By contrast, similar telemetric recordings were obtained in unrestrained Pkd1+/- and Pkd1+/+ mice. The contractile responses evoked by KCl or phenylephrine were similar in young animals but increased in abdominal aortas of 30-week-old Pkd1+/- mice, and acetylcholine-evoked relaxation was depressed. Basal cytosolic calcium, KCl, and phenylephrine-evoked calcium signals were significantly lower in the Pkd1+/- aortas, whereas calcium release evoked by caffeine or thapsigargin was significantly larger. These changes were paralleled with a significant change in the mRNA expression of Pkd2, Trpc1, Orai1, and Serca2a in the aortas from Pkd1+/- vs. Pkd1+/+. These results are the first to indicate that haploinsufficiency in Pkd1 is associated with altered intracellular calcium homeostasis and increased vascular reactivity in the aorta with compensatory changes in transport proteins involved in the calcium signaling network.
