Endothelium- and Fibroblast-Derived C-Type Natriuretic Peptide Prevents the Development and Progression of Aortic...

Thoracic (TAA) and abdominal (AAA) aortic aneurysm are life-threatening diseases characterized by dilation, inflammation, and structural weakness; development of pharmacological therapies is desperately needed. CNP (C-type natriuretic peptide) plays a key role in vascular homeostasis, mediating vasodilator, anti-inflammatory, and antiatherogenic actions. Since such processes drive AA, we determined the role of endogenous CNP in offsetting pathogenesis.

Tissue from patients with AA was analyzed to determine the consequences on CNP signaling. Ascending and suprarenal aortic diameters were assessed at baseline and following Ang II (angiotensin II; 1.44 mg/kg per day) infusion in wild-type, endothelium-restricted (ecCNP^-/-), fibroblast-restricted (fbCNP^-/-), global CNP (gbCNP^-/-), or global NPR-C^-/- mice infected with an adeno-associated virus expressing a proprotein convertase subtilisin/kexin type 9 gain-of-function mutation or backcrossed to an apoE^-/- background. At 28 days, aortas were harvested for RT-qPCR (quantitative reverse transcription polymerase chain reaction) and histological analyses. CNP (0.2 mg/kg per day) was infused to rescue any adverse phenotype.

Aneurysmal tissue from patients with TAA and AAA revealed that CNP and NPR-C (natriuretic peptide receptor-C) expression were overtly perturbed. ecCNP^-/-, fbCNP^-/-, and gbCNP^-/- mice exhibited an aggravated phenotype compared to wild-type animals in both ascending and suprarenal aortas, exemplified by greater dilation, fibrosis, elastin degradation, and macrophage infiltration. CNP and NPR-C expression was also dysregulated in murine thoracic AA and abdominal AA, accompanied by increased accumulation of mRNA encoding markers of inflammation, extracellular matrix remodeling/calcification, fibrosis, and apoptosis. CNP also prevented activation of isolated macrophages and vascular smooth muscle cells. An essentially identical phenotype was observed in NPR-C^-/- mice and while administration of CNP protected against disease severity in wild-type animals, this phenotypic rescue was not apparent in NPR-C^-/- mice.

Endothelium- and fibroblast-derived CNP, via NPR-C activation, plays important roles in attenuating AA formation by preserving aortic structure and function. Therapeutic strategies aimed at mimicking CNP bioactivity hold potential to reduce the need for surgical intervention.