Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces

BACKGROUND: The 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 RESULTS: We 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. CONCLUSIONS: We 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.Published versio

Changes in navigational behaviour produced by a wide field of view and a high fidelity visual scene

The difficulties people frequently have navigating in virtual environments (VEs) are well known. Usually these difficulties are quantified in terms of performance (e.g., time taken or number of errors made in following a path), with these data used to compare navigation in VEs to equivalent real-world settings. However, an important cause of any performance differences is changes in people’s navigational behaviour. This paper reports a study that investigated the effect of visual scene fidelity and field of view (FOV) on participants’ behaviour in a navigational search task, to help identify the thresholds of fidelity that are required for efficient VE navigation. With a wide FOV (144 degrees), participants spent significantly larger proportion of their time travelling through the VE, whereas participants who used a normal FOV (48 degrees) spent significantly longer standing in one place planning where to travel. Also, participants who used a wide FOV and a high fidelity scene came significantly closer to conducting the search "perfectly" (visiting each place once). In an earlier real-world study, participants completed 93% of their searches perfectly and planned where to travel while they moved. Thus, navigating a high fidelity VE with a wide FOV increased the similarity between VE and real-world navigational behaviour, which has important implications for both VE design and understanding human navigation. Detailed analysis of the errors that participants made during their non-perfect searches highlighted a dramatic difference between the two FOVs. With a narrow FOV participants often travelled right past a target without it appearing on the display, whereas with the wide FOV targets that were displayed towards the sides of participants overall FOV were often not searched, indicating a problem with the demands made by such a wide FOV display on human visual attention