Endothelial dysfunction and angiogenesis impairment in the ageing vasculature

Abstract

Ageing is the main risk factor for the development of cardiovascular diseases. A central mechanism by which ageing promotes vascular pathologies is compromising endothelial health. The age-related attenuation of endothelium-dependent dilator responses (endothelial dysfunction) associated with impairment of angiogenic processes and the subsequent pathological remodelling of the microcirculation contribute to compromised tissue perfusion and exacerbate functional decline in older individuals. This Review focuses on cellular, molecular, and functional changes that occur in the endothelium during ageing. We explore the links between oxidative and nitrative stress and the conserved molecular pathways affecting endothelial dysfunction and impaired angiogenesis during ageing. We also speculate on how these pathological processes could be therapeutically targeted. An improved understanding of endothelial biology in older patients is crucial for all cardiologists because maintenance of a competently functioning endothelium is critical for adequate tissue perfusion and long-term cardiac health.

Figure 1:. Proposed scheme for aging signaling pathways contributing to oxidative stress and endothelial dysfunction.

In aged endothelial cells increased levels of ROS generated by NOX oxidases (stimulated by elevated TNFα levels and/or by the activated local renin-angiotensin system [RAS] in the vascular wall) and mitochondria decrease the bioavailability of NO by forming ONOO-. Lack of NO leads to vasodilator dysfunction, whereas nitrative stress leads to PARP-1 activation, which contributes to NAD+ depletion. Impaired activity of NAD+ dependent pro-survival factor SIRT1 and the Nrf2-dependent antioxidant defense pathway exacerbates vascular oxidative stress and endothelial dysfunction in aging. The model predicts that in addition to these cell-autonomous mechanisms age-related deficiency of circulating IGF-1 and other vasoprotective factors confers pro-oxidative vascular effects in aging.

Figure 2:. Proposed scheme for the mechanisms by which aging impairs angiogenesis.

The proposed model predicts that aging both promotes intrinsic angiogenic incompetence in endothelial cells, rendering them unresponsive to inducers of angiogenesis and, simultaneously, fosters an anti-angiogenic microenvironment in the cardiac tissue.

Figure 3:. Aging promotes both intrinsic angiogenic incompetence in endothelial cells and dysregulated tissue expression of genes governing angiogenesis.

A-B) Intrinsic tube forming ability of microvascular endothelial cells isolated from aged, 24 month old F344xBN rats (B) is impaired as compared to that of cells isolated from young, 3 month old F344xBN (A). Adapted/Reproduced with permission from. Endothelial cells were plated on Geltrex matrix-coated wells and formation of capillary-like structures was induced by treating cells with VEGF (100 ng/ml, for 24 h). C-D) Aging leads to dysregulated expression of both positive- and negative regulators of angiogenesis in the heart. Data are from the published work of Yang et al., filtering for genes of interest (positive regulation of angiogenesis Gene Ontology Term [GO:0045766] and negative regulation of angiogenesis Gene Ontology Term [GO:0016525]) with mouse to human homology and sorted by the magnitude of age effect, based on a log2 fold change per year.