Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics

Abstract

Senescence compromises the essential role that the endothelium plays in maintaining vascular homeostasis, so promoting endothelial dysfunction and the development of age-related vascular diseases. Their biological and clinical significance calls for strategies for identifying and therapeutically targeting senescent endothelial cells. While senescence and endothelial dysfunction have been studied extensively, distinguishing what is distinctly endothelial senescence remains a barrier to overcome for an effective approach to addressing it. Here, we review the mechanisms underlying endothelial senescence and the evidence for its clinical importance. Furthermore, we discuss the current state and the limitations in the approaches for the detection and therapeutic intervention of target cells, suggesting potential directions for future research.

Endothelial Response to the Combined Biomechanics of Vessel Stiffness and Shear Stress Is Regulated via Piezo1

“…Endothelial senescence in aged and stiff vessels often is the underlying cause of vascular dysfunction and cardiovascular disorders. 9 Endothelial senescence is a dynamic and multistep process affecting cellular proliferation, and one of the major triggers of senescence is the activation of DNA damage response via the formation of the DNA damage foci containing activated γ-H2AX at either uncapped telomeres or persistent DNA strand breaks. 57,58 Here, assessing the combined effect of substrate stiffness and shear stress on endothelial cell proliferation and senescence, we find that although cellular proliferation increased on a stiff substrate regardless of shear stress, the activation of the senescence marker is only triggered under high shear stress conditions.…”

“…Endothelial senescence in aged and stiff vessels often is the underlying cause of vascular dysfunction and cardiovascular disorders . Endothelial senescence is a dynamic and multistep process affecting cellular proliferation, and one of the major triggers of senescence is the activation of DNA damage response via the formation of the DNA damage foci containing activated γ-H2AX at either uncapped telomeres or persistent DNA strand breaks. , …”

“…7 Endothelial senescence is a phenomenon in which endothelial cells halt their proliferation and undergo specific phenotypic alterations, resulting in a prothrombotic and proinflammatory state while also impairing vascular tone, angiogenesis, and vascular integrity. 8 Although the contribution of endothelial dysfunction, inflammation, and senescence in vascular stiffening has been previously reported, 7,9 it is not clear how changes in the vessel wall stiffness in the presence of hemodynamic forces affect endothelial biology, inflammation, and senescence. Furthermore, the identity of the mechanosensors that allow the endothelial cells to sense and respond to changes in vessel stiffness under different hemodynamic conditions is unknown.…”

Developmental priming of early cerebrovascular ageing: Implications across a lifetime

“…These studies showed limited BBB injury in younger and adult animals to either acute systemic or intracerebral inflammation, but a large BBB breakdown at intermediate postnatal ages 36,37 . This sensitivity has been found to recapitulate in the ageing brain, 38 adding to the idea of a natural vascular senescence 39 that may be accelerated by events throughout the lifetime and contributed to altered functioning of the BBB (or increased sensitisation to injury) in ageing 40 . Not every inflammatory or otherwise injurious event in the developing brain causes breakdown of the BBB, however; for instance, alterations in vascularisation of the developing brain following ZIKA infection have been shown without substantial evidence of altered barrier permeability 41,42 .…”

Mechanisms of Vascular Inflammation and Potential Therapeutic Targets: A Position Paper From the ESH Working Group on Small Arteries

“…Various cardiovascular and metabolic disorders are linked with vascular inflammation, including diabetes, obesity, hypercholesterolemia, senescence, and aging, which have already been well discussed in recent publications. [30][31][32][33][34][35] In this article, we provide a current overview and concepts about inflammatory mechanisms and epigenetic modifications in the vasculature and their contribution to vascular injury associated to hypertension and neurodegenerative diseases. Finally, we synthesize current evidence to demonstrate how these pathways may represent novel therapeutic targets, offering promising avenues for the treatment of vascular disorders.…”