Interaction between vascular-lymphatic system imbalance and immune microenvironment in intervertebral disc degeneration

Abstract

BACKGROUND: The pathological process of intervertebral disc degeneration is accompanied by angiogenesis-lymphatic imbalance and changes in the immune microenvironment, both of which play important roles in intervertebral disc degeneration. OBJECTIVE: To systematically summarize the roles of angiogenesis-lymphatic imbalance-related cytokines in intervertebral disc degeneration. METHODS: The first author searched relevant literature published between January 2000 and April 2025 in the PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. The Chinese search terms included "intervertebral disc degeneration, vascular-lymphatic imbalance, angiogenesis, vascular endothelial growth factor (VEGF), lymphatic vessel, Prox-1, immune microenvironment." A total of 65 articles were ultimately included for review. RESULTS AND CONCLUSION: During intervertebral disc degeneration, the vascular-lymphatic system and immune microenvironment play crucial roles in maintaining disc homeostasis. When disc degeneration occurs, angiogenesis and lymphatic disruption increase inflammatory factors within the disc, leading to enhanced degradation of the extracellular matrix. Concurrently, changes in the immune microenvironment, characterized by increased immune cell infiltration, elevated levels of pro-inflammatory cytokines and chemokines, and activation of local immune responses, modulate vascular and lymphatic vessels, ultimately reducing disc repair capacity and inducing chronic pain, thereby exacerbating the degree of disc degeneration.

1. Introduction

Intervertebral disc degeneration is a major cause of chronic low back pain and neurological dysfunction, imposing a huge burden on social economy and public health. The intervertebral disc is composed of the nucleus pulposus, annulus fibrosus, and cartilaginous endplates, with unique blood supply characteristics. FOURNIE et al. [1] conducted a retrospective study on human intervertebral disc vascularization, pointing out that the cartilaginous endplates and annulus fibrosus have abundant blood supply early in life, but with aging, the blood supply gradually decreases, while the nucleus pulposus never develops blood vessels throughout life. The growth of blood vessels into the cartilaginous endplates and inner annulus fibrosus is usually associated with disc injury or tissue destruction, indicating that the degenerative process of the disc is often accompanied by abnormal angiogenesis.

Traditional views held that the adult intervertebral disc is avascular and alymphatic [2], with nutrition mainly provided by passive diffusion through the cartilaginous endplates. Recently, researchers have for the first time localized the expression of lymphatic vessel-specific markers, such as Prox-1 and LYVE-1, in the annulus fibrosus of healthy human intervertebral discs, revealing clear tubular lymphatic structures [3], overturning the previous understanding. During disc degeneration, neovascularization, increased vascular permeability, and reduced lymphatic vessel number lead to vascular-lymphatic imbalance and local immune microenvironment changes, exacerbating the degree of disc degeneration [3-6]. Simultaneously, immune microenvironment changes activate immune cells, affecting vascular-lymphatic imbalance and further aggravating disc degeneration. The interaction between vascular-lymphatic imbalance and immune microenvironment changes accelerates the progression of disc degeneration (Figure 1). This article summarizes the factors related to vascular-lymphatic imbalance, immune microenvironment changes and their effects, and the synergistic role of both in disc degeneration (Figure 2), aiming to provide new perspectives for research on the mechanisms of disc degeneration.