One of the many possible approaches to tinkering with cell behavior is to produce non-functional but otherwise safe copies of a particular protein and introduce them into the patient. The non-functional proteins compete with the natural functional proteins, and thus interfere in whatever it is that the functional proteins are trying to achieve. This is an alternative to approaches that involve directly reducing levels of the functional protein in some way.
Here researchers employ this approach to provide initial evidence that suppressing the activity of the protein N-WASP can reduce stiffness in blood vessels. This protein is a link between signal molecules received at the cell surface and consequent changes in the behavior of the cytoskeleton of the cell, so interference here desensitizes the cell to received signals that may be instructing it to act in ways that stiffen the tissue.
This is a form of compensatory interference that is a long way removed from the varied origins of the problem of stiffening of blood vessels with age. It won't do much for fraction of stiffness that results from origins exterior to cells, such as cross-linking or loss of elastin in the extracellular matrix. It is nonetheless quite interesting as a technology demonstration: the signals that induce the unhelpful cell behavior in blood vessel walls that contributes to stiffness are nowhere near fully mapped and understood, and this may be a way to bypass that lack of understanding. That is incrementally better than not bypassing it, even if it is still not a way to address the root causes of altered cell behavior.
Vascular aging is associated with impaired endothelial function, low-grade inflammation, and markedly increased aortic stiffness. Aging is associated with fragmentation of elastin and increased amounts and cross-linking of collagen, all of which increase the passive stiffness of the extracellular matrix. However, it has also been proposed that aging of the vascular smooth muscle cell (VSMC) can adversely modulate the fractional engagement of collagen, leading to a dynamic increase in stiffness. In fact, recent studies in a mouse model, where viable smooth muscle preparations can be readily obtained and activated with vasoactive agents to measure active stiffness, have demonstrated that close to half of the total stiffness of the aortic wall is attributable to the active stiffness of the VSMC, with the remaining fraction due to the extracellular matrix.
In addition to the passive stiffness of the matrix, there are at least two dynamic components that contribute to the material stiffness of the VSMC: first, the attachment of cycling crossbridges in the contractile filaments, and, second, the regulated transmission of force and stiffness through a nonmuscle actin cytoskeleton connected to focal adhesion (FA) complexes. The stiffness and plasticity of this nonmuscle actin cytoskeleton are regulated by proteins that control branched and linear actin polymerization such as N-WASP and VASP, respectively.
The nonmuscle actin cytoskeleton and FAs to which it is attached have been shown to display plasticity. Plasticity of the cortical cytoskeleton of VSMCs may contribute to the function of the healthy, compliant proximal aorta, acting as a tunable "shock absorber" that adapts in order to limit transmission of excessive pulsatile energy into the delicate downstream microvessels. This plasticity of the cortical cytoskeleton of the aorta in young mice has been shown to utilize a Src-dependent signaling pathway that promotes tyrosine phosphorylation of FA proteins. We have found that attenuated activity of this pathway with aging is associated with stiffening, measured ex vivo in a mouse model.
In the present study we tested the hypothesis that specific cytoskeletal protein-protein interfaces that no longer remodel in the aged aorta could be competed with by decoy peptides to reduce increases in aortic stiffness of proximal aortas taken from aged mice. 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.