Key result
CRTC1 deficiency in male mice caused high blood pressure and autonomic dysregulation before obesity onset, reversed by α1-adrenoceptor blockade with prazosin but not β1-blockade with metoprolol.
Why the study?
The causal mechanisms linking cardiovascular disease, sympathetic overactivity, obesity, and depression remain unknown. Although CRTC1-deficient mice exhibit depression-related behavior and metabolic syndrome features, whether global CRTC1 deficiency is also associated with arterial hypertension had not been determined.
Does global CRTC1 deficiency cause arterial hypertension and autonomic dysregulation in male mice?
Does global CRTC1 deficiency cause arterial hypertension and autonomic dysregulation in male mice?
Global CRTC1 deficiency in male mice induces arterial hypertension driven by autonomic dysregulation and peripheral alpha-1-adrenoceptor-mediated vasoconstriction, linking central signaling pathways to the comorbidity of metabolic syndrome and depression.
Should not yet change practice; leaves open CRTC1 pathways in human autonomic hypertension.
Epidemiological evidence links cardiovascular disease, sympathetic nervous system overactivity, obesity, and depression. Whether this association is causal and what mechanisms may be involved remains unknown. Mice deficient in the CREB-regulated transcription coactivator 1 (CRTC1) show depression-related behavior and a metabolic profile resembling the metabolic syndrome. This study aimed to characterize arterial blood pressure regulation in these mice to determine whether global CRTC1 deficiency is also associated with arterial hypertension, another key characteristic of the metabolic syndrome. Telemetric measurements in unrestrained male mice revealed high blood pressure in Crtc1-deficient animals before the onset of obesity or hypertrophy of arterioles, accompanied by decreased heart rate variability, increased systolic blood pressure variability, enhanced environmental stress sensibility, and increased urinary catecholamine excretion. Pharmacological α 1 -adrenoceptor blockade with prazosin induced greater blood pressure reductions in Crtc1-deficient mice and eliminated genotype-dependent pressure differences, whereas the β 1 -adrenoceptor antagonist metoprolol showed no genotype-specific effect. Regulation of renal sodium transport proteins, activity of the renin-aldosterone system, and cardiac systolic function were unchanged between genotypes. Crtc1-deficient animals also exhibited impaired glucose tolerance and a depression-related phenotype associated with reduced locomotion, increased agmatinase, and decreased cerebral Bdnf and c-fos expression. These findings indicate that CRTC1 deficiency leads to high blood pressure likely driven by excessive peripheral α 1 -adrenoceptor-mediated vasoconstriction caused by autonomic dysregulation. The co-occurrence of increased blood pressure, metabolic dysregulation, and the depressive-like phenotype in male Crtc1-deficient mice suggests a regulatory role of CRTC1 in the complex central network of signaling pathways involved in the frequent comorbidity of metabolic syndrome and depression.
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Morhenn et al. (2026) studied Arterial hypertension, metabolic syndrome, and depression-related phenotype. Global CRTC1 deficiency (with prazosin α1-adrenoceptor and metoprolol β1-adrenoceptor challenges) vs. Wild-type control genotype was evaluated on Arterial blood pressure regulation and autonomic function. CRTC1 deficiency in male mice caused high blood pressure and autonomic dysregulation before obesity onset, reversed by α1-adrenoceptor blockade with prazosin but not β1-blockade with metoprolol.
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