Functional, Structural and Proteomic Effects of Ageing in Resistance Arteries

Abstract

The normal ageing process affects resistance arteries, leading to various functional and structural changes. Systolic hypertension is a common occurrence in human ageing, and it is associated with large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, a progressive elevation in the mean arterial pressure is evidenced by clinical and epidemiological data as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. The dysregulation of calcium entry channels (L-type, T-type, and TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to the age-related dysregulation of myogenic tone. Flow-mediated vasodilation, a hallmark of endothelial function, is compromised in ageing. This endothelial dysfunction is related to increased oxidative stress, lower nitric oxide bioavailability, and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall that is typically observed in conjunction with outward remodeling (in normotension), or as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of actin cytoskeletal components, and extracellular matrix fiber proteins. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation play substantial roles in age-related vascular dysfunction. Due to its role in the regulation of vascular tone and structural proteins, the RhoA/Rho-kinase pathway is an important target in age-related vascular dysfunction and diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance the overall vascular health.

Keywords: ageing; cardiovascular disease; flow-mediated vasodilation; hypertension; myogenic tone; neurodegenerative disease; proteomics; resistance artery; structural remodeling.

Figure 1

Protein–protein interaction network. The proteins in Table 1 were analyzed using STRING database to show their respective physical and functional interactions with medium confidence level (Score ≥ 0.400). See Table for definition of symbols.

Figure 2

Summary of age-dependent changes in myogenic tone, flow-mediated vasodilation, and structural remodeling in resistance arteries. Green text and arrows to the left denote vasomotor tone at young age with a normal MT and FMVD. Red text and arrows in the middle denote changes to vasomotor tone during ageing. Upper part denotes decreased myogenic tone but no change in FMVD leading to vasodilation. Lower part denotes decreased FMVD but no change in MT leading to vasoconstriction. Blue text and arrows to the right denote chronic changes due to remodeling during ageing. Upper part shows the final remodeling outcome with a normal blood pressure, and lower part shows the final remodeling outcome in case of co-existing hypertension. See text for further explanations. The inner endothelial (intima) layer is shown as gray-blue, the smooth muscle (media) layer is shown as pink, and the connective tissue (adventitia) layer is shown in yellow color. Arrows denote the direction of change in a function, factor, or parameter. MT (myogenic tone); FMVD (flow-mediated vasodilation); D_L (passive lumen diameter); CSA (cross-sectional area); M/L-ratio (media:lumen-ratio); ROS (reactive oxygen species); NO (nitric oxide); VGCC (voltage-gated calcium channel); TRP (transient receptor potential channel).