What are VEGF and SDF-1?
Vascular Endothelial Growth Factor (VEGF) is a potent angiogenic glycoprotein that promotes endothelial cell proliferation, migration, and tube formation, serving as the key mediator of new blood vessel formation, while Stromal Cell-Derived Factor-1 (SDF-1) is a chemokine that recruits CXCR4-positive cells to sites of angiogenesis and works synergistically with VEGF to enhance vascular repair and neovascularization. 1
Vascular Endothelial Growth Factor (VEGF)
Basic Structure and Function
VEGF is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa that binds to two primary receptors (VEGF receptor-1/flt-1 and VEGF receptor-2/flk-1) expressed on vascular endothelial cells 2
VEGF promotes three critical endothelial cell functions: proliferation, migration, and tube formation, making it the most potent inducer of angiogenesis 1
VEGF induces vascular permeability and endothelium-dependent vasodilation in association with endothelium-derived nitric oxide, which is essential for vessel remodeling 1
Physiological Roles
In healthy individuals, VEGF promotes angiogenesis during embryonic development and is critical for wound healing in adults 2
VEGF plays an essential role in glomerular capillary repair following endothelial cell damage, as demonstrated in experimental nephritis models 1
VEGF expression is primarily localized to glomerular podocytes in the kidney, where signals from these cells attract sprouting capillaries to sites beneath the glomerular basement membrane 1
Pathological Significance
VEGF is the key mediator of angiogenesis in cancer, where it is upregulated by oncogene expression, growth factors, and hypoxia 2
Tumors require VEGF-induced angiogenesis to grow beyond 1-2 mm, as they need blood vessels for nutrients and oxygen delivery 2
Tumor vasculature formed under VEGF influence is structurally abnormal: vessels are irregularly shaped, tortuous, leaky, and hemorrhagic, leading to high interstitial pressure and suboptimal blood flow 2
Stromal Cell-Derived Factor-1 (SDF-1)
Basic Function and Mechanism
SDF-1 (also known as SDF-1α) is a chemokine that recruits CXCR4-positive bone marrow-derived circulating cells to sites of tissue ischemia and angiogenesis 3, 4
SDF-1 is expressed in endothelial and subendothelial cells, while its receptor CXCR4 is expressed in proximity to capillaries 4
SDF-1 enhances endothelial progenitor cell adhesion and migration by two- to sixfold in vitro and nearly doubles their recruitment to both ischemic and nonischemic muscle tissue in vivo 3
Role in Vascular Repair
SDF-1 works synergistically with VEGF to promote lumen formation in 3D collagen matrices, with the combination of growth factors (including SDF-1α, FGF-2, SCF, and IL-3) optimizing endothelial tube formation under serum-free conditions 1
VEGF-induced SDF-1 expression recruits CXCR4-positive cells with paracrine functions that support angiogenesis in ischemic tissues 4
Local delivery of VEGF and SDF-1 from biomaterial scaffolds significantly improves functional perfusion recovery in ischemic limbs when combined with systemic endothelial progenitor cell delivery 3
Expression Patterns in Disease
In chronic ischemia, VEGF, SDF-1, and CXCR4 expressions are generally decreased (0.41-fold, 0.97-fold, and 0.54-fold median induction, respectively) compared to nonischemic muscle 4
In acute-on-chronic ischemia, these factors are substantially increased (3.5- to 65.8-fold for VEGF, 3.9- to 19.0-fold for SDF-1, and 4.1- to 30.6-fold for CXCR4), correlating strongly with capillary area 4
Synergistic Interaction Between VEGF and SDF-1
Coordinated Angiogenic Response
The appropriate balance between VEGF and angiopoietins (Ang-1/Ang-2) is critical for proper blood vessel formation, with coexpression of VEGF and Ang-1 resulting in enhanced angiogenesis with formation of nonleaky blood vessels 1
VEGF acts as a powerful attractor of bone marrow-derived mononuclear cells bearing myeloid and endothelial markers to sites of neovascularization, though these cells are not incorporated into newly formed vessels 5
The VEGF-SDF-1-CXCR4 pathway represents a promising therapeutic target for treating chronic ischemic disease through perivascular retention of CXCR4-positive cells 4
Clinical Implications
Biomaterial-based local delivery of VEGF and SDF-1 can enrich accumulation of infused endothelial progenitors and improve therapeutic outcomes in ischemic cardiovascular disease 3
Circulating angiogenic cells (CACs) are more responsive to VEGF and SDF-1 treatment than outgrowth endothelial cells (OECs), promoting endothelial sprout formation more potently and demonstrating greater influence on infiltrating inflammatory cells 3