Abstract 059: Local Endothelial and Smooth Muscle Genomic Instability Reproduce Specific Features of Cardiovascular Aging

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 72; no. Suppl_1
• Main Authors: Bautista-Nino, Paula Katherine, Portilla-Fernandez, Eliana, Santu, Alexandra, Shanahan, Catherine, Roks, Anton
• Format: Journal Article
• Language: English
• Published: 01-09-2018
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.72.suppl_1.059

Abstract only
Nuclear and mitochondrial DNA damage contribute to aging and related cardiovascular disease. To explore if the aging features are cell autonomous we compared cardiovascular function of mice with a specific DNA repair system knockout in vascular endothelial cells (EC-KO) to that of mice with specific knockout in smooth muscle cells (SMC-KO). We evaluated cardiac function by echocardiography, blood pressure by the tail cuff method and
ex vivo
vascular function in aorta, coronary and carotid arteries using wire myographs organ baths setups. EC-KO showed macrovascular and microvascular vasodilator dysfunction due to specific loss of endothelium-dependent nitric oxide (NO) signaling (maximal vasorelaxation response to acetylcholine in aorta: 59.0% in EC-KO vs 75.0% in WT mice; p-value lt 0.0001). The reduction of vasodilator response was associated with a temporary systolic blood pressure increase at 3 months (138 mm Hg in EC-KO vs 125 mm Hg in WT mice; p-value= 0.03). In addition, EC-KO mice showed a severely compromised microvascular barrier function in the kidney, leading to papillary necrosis. Cardiac output was slightly affected at 5 months of age (16 ml/min in EC-KO vs 18 ml/min in WT mice; p-value= 0.13) and aortic distensibility was reduced (0.2 mm in EC-KO vs 0.3 mm in WT mice; p-value =0.05), suggesting decreased cardiac contractility and increased vascular stiffness. In sharp contrast, SMC-KO mice showed a specific decrease of endothelium-independent NO-mediated relaxation (maximal vasorelaxation response to the NO donor sodium nitroprusside: 83.4% in SMC-KO vs 98.6% in WT mice; p-value lt 0.001). Furthermore, SMC-KO showed increased carotid artery stiffness (Mediastress at intraluminal pressure of 120 mm Hg: 1.44*10
6
in SMC-KO vs 1.82*10
6
dyness/cm
2
in WT mice; p-value lt 0.001), displayed aortic root dilation and regurgitation. We conclude that DNA damage in EC and VSMC each lead to specific pathological changes that are found also in human cardiovascular aging. In complement, the changes reproduce the vascular phenotype of whole body DNA repair knockout mice (
Ercc1
d/-
) previously found by us. Therefore, the cardiovascular aging effects of DNA damage are at least partly cell autonomic, and represent an important treatment target.