Impaired angiogenesis in ageing: the central role of the extracellular matrix

Abstract

Each step in angiogenesis is regulated by the extracellular matrix (ECM). Accumulating evidence indicates that ageing-related changes in the ECM driven by cellular senescence lead to a reduction in neovascularisation, reduced microvascular density, and an increased risk of tissue ischaemic injury. These changes can lead to health events that have major negative impacts on quality of life and place a significant financial burden on the healthcare system. Elucidating interactions between the ECM and cells during angiogenesis in the context of ageing is neceary to clarify the mechanisms underlying reduced angiogenesis in older adults. In this review, we summarize ageing-related changes in the composition, structure, and function of the ECM and their relevance for angiogenesis. Then, we explore in detail the mechanisms of interaction between the aged ECM and cells during impaired angiogenesis in the older population for the first time, discussing diseases caused by restricted angiogenesis. We also outline several novel pro-angiogenic therapeutic strategies targeting the ECM that can provide new insights into the choice of appropriate treatments for a variety of age-related diseases. Based on the knowledge gathered from recent reports and journal articles, we provide a better understanding of the mechanisms underlying impaired angiogenesis with age and contribute to the development of effective treatments that will enhance quality of life.

Keywords: Ageing; Angiogenesis; Endothelial cell; Extracellular matrix; Pericyte; Therapeutic angiogenesis treatments.

Fig. 1

The tube-forming ability of microvascular endothelial cells (ECs) isolated from 3-month-old F344xBN rats (A) is greater than that of cells isolated from 24-month-old rats (B) [141]

Fig. 2

Normal and ageing-affected extracellular matrix (ECM). As compared with normal ECM (left), the composition and structure of ageing-affected ECM (right) are altered, and the matrix stiffness is greater

Fig. 3

Mechanisms of interaction of ageing-affected ECM with ECs and pericytes during angiogenesis. In younger adult ECM (top), the softer matrix interacts with ECs to promote survival, proliferation, migration, and differentiation, and there is neovascular growth from blood vessels, forming a vascular lumen that interacts with pericytes, leading to pericyte recruitment and promoting neovascular maturation. In ageing-affected ECM (bottom), the rigid matrix interacts with ECs to promote apoptosis and reduce the proliferation, migration, and differentiation capacity of ECs, leading to a decrease in neovascular growth. In addition, the interaction with pericytes leads to a decrease in the capacity for pericyte recruitment and a reduction in the ability of the neovasculature to mature and stabilize