Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

Abstract

BackgroundThe proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening.Methods and ResultsWe examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome‐wide association study of carotid‐femoral pulse wave velocity. Common genetic variation in the N‐WASP (WASL) locus is associated with carotid‐femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N‐WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N‐WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin‐vinculin interfaces similarly decreased aging‐induced ex vivo active stiffness by on‐target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound‐targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness.ConclusionsWe conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein‐protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein‐protein interfaces may lead to substantive dynamic modulation of aortic stiffness.

The brains of aged mice are characterized by altered tissue diffusion properties and cerebral microbleeds

“…In both rodents and humans the stiffness of the proximal aorta increases with age, augmenting systolic blood pressure (BP) pulsatility and increasing the risk of CV events [ 21 – 23 ]. The proximal aorta is hypothesized to be a shock absorber, but with age, high pulses of pressure that can damage the brain microvasculature are sent to the small delicate blood vessels downstream [ 24 , 25 ].…”

“…For example, CMBs, also known as microhemorrhages, are biomarkers of aging, hypo-intense on GRE MRI, associated with geriatrics, cognitive impairment, and risk of stroke [17][18][19][20]. As the stiffness of the proximal aorta increases with age, [21][22][23] high pulses of pressure are sent to the small delicate blood vessels downstream. These pulses could damage the cerebral vessel walls in a way that increases leaking of blood into vulnerable brain regions, a possible mechanism for CMBs formation [24,25].…”

Aortic stiffness, pressure and flow pulsatility, and target organ damage

“…Thus stiffening can interfere with flow-mediated dilation, both by the reduction of the hyperemic stimulus and by the production of abnormal flow patterns that adversely affect endothelial function. Conversely, abnormal endothelial function may modulate aortic stiffness by the alteration of the activation state of smooth muscle in the aortic wall (74), resulting in the potential for a vicious cycle of stiffening and endothelial dysfunction. As a result of the foregoing effects, blunted microvascular hyperemia is associated with CVD events and partially mediates the relation between aortic stiffness and CVD events (1,25).…”

Vascular aging, the vascular cytoskeleton and aortic stiffness

“…More recently, it has been shown that the vascular smooth muscle cell (VSMC) [14][15][16][17] also undergoes aging-dependent changes that increase its stiffness and, as a result, the stiffness of the aortic wall. Within the VSMC, the activity of the contractile filaments as well as the molecular signaling pathways that regulate actin polymerization and focal adhesion (FA) signaling, are sources of increases in vascular stiffness with age [18]. It has only recently been recognized that regulation of the stiffness of the cytoskeleton of the VSMC can contribute up to 50% of total aortic stiffness even in young adult aortas in mouse models [16].…”