PDI Overexpression Improves Vascular Contractility in Aged Blood Vessels
A broad range of mechanisms contribute to a growing stiffening of blood vessels, a loss of ability to contract and dilate in response to environmental cues. Blood flow is vital, and this impairs its regulation. Vascular stiffening contributes to hypertension, atherosclerosis, and downstream issues in the cardiovascular system the tissues it supports. One of the causes of vascular stiffening is progressive inability of the smooth muscle surrounding vessels to sufficiently constrict the vessel. This dysfunction arises from its own grab bag of various mechanisms with various much debated degrees of importance relative to one another.
Today's open access paper is a dive into one specific aspect of the biochemistry of smooth muscle activity. The researchers characterize a particular age-related issue related to regulation of the cytoskeletal structure of vascular smooth muscle cells and its relationship to oxidizing molecules in the context of vessel constriction. The point to all of this is that the researchers demonstrate that age-related loss of the ability of smooth muscle tissue to constrict vessels can be reversed to some degree by overexpression of a specific protein involved in their mechanisms of interest. The best way to justify further investigation of a novel mechanism is by demonstrating its relevance in living tissues.
A mechanism for the disrupted redox regulation of vascular contractility during aging
Aging of vascular cells significantly contributes to the overall organismal aging phenotype and is a major independent risk factor for cardiovascular diseases. While many studies focused on endothelial cells, aging-related processes also affect the vascular smooth muscle cell (VMSC). An aged VSMC associated with disturbed arterial stiffness and, in particular, impaired contractility.
Cytoskeletal deregulation, mainly of the actin network, lies at the core of such changes. Importantly, cytoskeleton-linked mechanobiological processes strongly crosstalk with redox-dependent signaling at several levels, from sensing to tissue remodeling. In particular, an oxidant environment promotes actin polymerization and enhances contractility. It is conceivable, thus, that post-translational redox modifications, including e.g., protein sulfenylation, affect actin organization, but the precise role of such an oxidant environment on vascular contractility during aging is unknown.
We hypothesized that the aging-related impairment of redox and sulfenylation-regulated cytoskeleton dynamics associates with the disruption of chaperone signaling. A particular subgroup of redox chaperones is the protein disulfide isomerases, with prominence of its founding member PDIA1 (or simply PDI). This thioredoxin superfamily protein is mainly located in the endoplasmic reticulum (ER), where it supports oxidative protein folding. Meanwhile, it also exhibits functions out of the ER associated with mechano-regulation, including fine-tuning of cellular force distribution, integrin regulation, and β-actin organization, accounting for vascular remodeling modulation
We first show that protein sulfenylation supports vascular contractility and F-actin assembly during mechanoadaptation or agonist-induced contraction. Meanwhile, PDI supports sulfenylation-dependent actin remodeling. Moreover, aged murine arteries lose the sulfenic acid-related component of contractility, while PDI overexpression overrides this dysfunction and restores aging-related vascular contractility. We further confirm a direct PDI-actin interaction modulated by sulfenic acid. Overall, signaling connections between PDI and sulfenylated proteins behave as an upstream integrative system regulating F-actin assembly, a mechanism that is impaired during aging-induced vascular dysfunction.