Endothelial senescence of the vertebral artery in the context of cervical degeneration: biomechanically driven remodeling of the hemodynamic environment

Figures

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  FIGURE 1. Mechanistic network underlying endothelial senescence and its functional consequences. Endothelial senescence arises from both replicative exhaustion and environment-driven stress, including disturbed flow, mechanical stress, metabolic imbalance, and chronic inflammation. These stimuli converge on the activation of the DNA damage response characterized by γH2AX accumulation and p53/p21 signaling, and are further reinforced by telomere dysfunction. Metabolic remodeling, including mitochondrial dysfunction, NAD+ decline, and reduced SIRT1 activity, promotes the accumulation of ROS, which in turn amplifies DNA damage and senescence signaling. Impairment of autophagy further contributes to the persistence of damaged organelles and oxidative stress.

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  FIGURE 2. Disturbed shear stress drives endothelial senescence:Laminar shear stress activates the MEF2–KLF2/KLF4 pathway to maintain endothelial homeostasis. In contrast, disturbed flow suppresses this protective signaling through HDAC5/7 and activates integrin–FAK–SRC–YAP/TAZ pathways, promoting oxidative stress, DNA damage, and p53–p21–mediated cell-cycle arrest, ultimately leading to endothelial senescence and vascular dysfunction.

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  FIGURE 3. From cervical degeneration to endothelial senescence: remodeling of the vertebral artery microenvironment. This schematic illustrates how chronic structural and biomechanical changes associated with cervical spine degeneration reshape the vertebral artery microenvironment and ultimately promote endothelial senescence and functional vulnerability of the posterior circulation. Cervical degenerative changes, including intervertebral disc degeneration, osteophyte formation, and altered segmental mobility, impose persistent biomechanical constraints on the vertebral artery. These structural conditions lead to alterations in vascular geometry, spatial confinement, and repetitive fluctuations in shear stress and perfusion. Under these conditions, endothelial mechanotransduction pathways—including the MEF2–KLF2/KLF4 axis, HDAC5/7 nuclear translocation, YAP/TAZ activation, and metabolic stress signaling involving AMPK/SIRT1, eNOS, and reactive oxygen species—contribute to transcriptional reprogramming and the stabilization of endothelial senescence through p53/p21 signaling. The cumulative effect of these processes is a progressive decline in vascular functional adaptability, impaired…

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  FIGURE 4. Conceptual model linking cervical degeneration, vertebral artery hemodynamics, and posterior circulation vulnerability. Cervical degeneration may influence vertebral artery function through multiple parallel pathways, including direct mechanical compression, alteration of vascular geometry, and motion-related dynamic stress. These factors can independently or synergistically contribute to hemodynamic instability, characterized by disturbed flow patterns, and reduced effective shear stress. The resulting environment may promote endothelial dysfunction and senescence, leading to a reduction in vascular functional reserve. In this framework, clinical manifestations are not determined solely by the degree of mechanical compression, but rather emerge from the integration of multiple biomechanical inputs and the functional state of the endothelium.