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Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF), primarily referring to VEGF-A, is a homodimeric glycoprotein that serves as a key regulator of angiogenesis—the formation of new blood vessels from pre-existing vasculature—and a potent inducer of vascular permeability.^[1] First identified in 1983 as a vascular permeability factor (VPF) derived from tumor cells, VEGF was cloned in 1989 and recognized as an endothelial cell-specific mitogen essential for physiological and pathological vascular processes.^[1] Its primary biological roles include promoting endothelial cell proliferation, migration, and survival, thereby supporting embryonic vasculogenesis, tissue repair, and wound healing, while also exhibiting neurotrophic and neuroprotective effects in the nervous system.^[1]^[2] The VEGF family encompasses five structurally related ligands: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), each with distinct but overlapping functions in vascular biology.^[3] VEGF-A, the most studied member, exists in multiple isoforms generated by alternative splicing, such as VEGF-A₁₂₁ (diffusible and non-heparin-binding), VEGF-A₁₆₅ (the predominant form with balanced heparin affinity), and longer isoforms like VEGF-A₁₈₉ and VEGF-A₂₀₆ that exhibit increased matrix binding.^[1] VEGF-B primarily influences vascular endothelial function in metabolic contexts, VEGF-C and VEGF-D drive lymphangiogenesis, and PlGF modulates angiogenesis in pathological settings, often synergizing with VEGF-A.^[2] These ligands bind to three tyrosine kinase receptors—VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4)—with VEGFR-2 mediating the core angiogenic signals through pathways like MAPK/ERK and PI3K/Akt.^[3] Coreceptors such as neuropilins enhance signaling specificity and potency.^[1] In health, VEGF signaling is tightly regulated to ensure proper embryonic vascular development, maintain endocrine organ fenestration (e.g., in the thyroid), and facilitate cyclic processes like menstruation and ovulation.^[2] Dysregulation, however, contributes to numerous diseases: in cancer, hypoxic tumors upregulate VEGF-A via hypoxia-inducible factor-1α (HIF-1α) to fuel neovascularization and metastasis; in ocular disorders like diabetic retinopathy and age-related macular degeneration (AMD), it drives pathological retinal angiogenesis; and in cardiovascular conditions, it plays dual roles in atherosclerosis progression and ischemic repair.^[2] Additionally, elevated VEGF levels are implicated in inflammatory diseases such as rheumatoid arthritis and metabolic disorders including diabetic nephropathy.^[2] Therapeutically, VEGF's central role in pathological angiogenesis has led to the development of anti-VEGF agents, revolutionizing treatments for oncology and ophthalmology since the approval of bevacizumab in 2004 for colorectal cancer and subsequent drugs like ranibizumab and aflibercept for AMD and diabetic macular edema, with newer agents such as faricimab (approved 2022, a bispecific antibody targeting VEGF-A and Ang-2) and high-dose aflibercept formulations offering extended durability as of 2025.^[2]^[4] These monoclonal antibodies and receptor traps inhibit ligand-receptor interactions, reducing tumor vascularization and leakage in retinal diseases, though challenges like resistance, cardiovascular side effects, and the need for biomarkers persist.^[2] Ongoing research explores VEGF's broader immunomodulatory effects and potential in regenerative medicine, underscoring its multifaceted impact on human physiology and disease.^[2]

Discovery

Early Observations

In the 1930s, researchers began documenting increased vascular permeability as a hallmark of inflammation, attributing it to endogenous factors released in response to injury. Valy Menkin identified a substance in inflammatory exudates that rapidly enhanced capillary permeability, challenging the prevailing histamine hypothesis and suggesting the involvement of distinct mediators in inflammatory responses.^[5]^[6] By the 1960s, studies on mild thermal injury further supported the existence of endogenous permeability factors, demonstrating that inflammation-induced vascular leakage persisted independently of histamine and involved soluble mediators that altered endothelial barriers.^[7] These observations laid groundwork for understanding how tissue injury and repair processes, including wound healing, relied on modulated vascular permeability to facilitate immune cell infiltration and nutrient delivery, though specific factors remained unidentified.^[8] In the 1970s, Judah Folkman advanced these concepts through pioneering experiments on tumor angiogenesis, proposing that solid tumor growth is strictly dependent on the induction of new blood vessel formation. Folkman's tumor dormancy model illustrated that microscopic tumors could remain avascular and quiescent for extended periods, limited by diffusion of nutrients, until they secreted diffusible angiogenic factors that triggered vascular ingrowth, enabling exponential expansion.^[9] His 1971 hypothesis in the New England Journal of Medicine posited that tumors produce a soluble "tumor angiogenesis factor" (TAF) to stimulate endothelial proliferation, shifting the paradigm from uncontrolled tumor autonomy to a regulated angiogenic process amenable to therapeutic inhibition. Experimental implantation of tumor fragments into isolated vascular beds confirmed this dependency, as tumors failed to grow beyond 1–2 mm³ without neovascularization.^[10] The 1980s saw key studies elucidating hypoxia as a potent driver of vascular responses in animal models, setting the stage for angiogenic factor discovery. Experiments in chick chorioallantoic membranes exposed to chronic hypoxia demonstrated increased vascular density and endothelial proliferation, indicating that low oxygen tension directly stimulates angiogenesis independent of other stimuli.^[11] Concurrently, in 1983, Harold Dvorak and colleagues identified a vascular permeability factor (VPF) in tumor ascites fluids from guinea pigs, hamsters, and mice, which rapidly increased microvascular permeability by up to 50,000-fold within minutes, far exceeding histamine's effects.^[12] This factor, secreted by tumor cells, was hypothesized to facilitate plasma protein extravasation and fibrin deposition, creating a provisional matrix essential for neovessel invasion and tumor progression.^[12] These findings bridged earlier permeability observations with tumor-induced vascular changes, highlighting VPF's role in both pathological and physiological contexts like wound healing.

Molecular Identification

The molecular identification of vascular endothelial growth factor (VEGF) marked a pivotal advancement in understanding angiogenesis, building on prior observations of tumor-derived angiogenic factors. In 1989, Napoleone Ferrara and colleagues at Genentech purified a novel heparin-binding mitogen specific to vascular endothelial cells from media conditioned by bovine pituitary folliculostellate cells, yielding a homodimeric glycoprotein with an apparent molecular weight of 45-50 kDa under non-reducing conditions and 21-24 kDa subunits under reducing conditions on SDS-PAGE.^[13] This purification distinguished the factor from other known growth factors like basic fibroblast growth factor (bFGF), highlighting its selectivity for endothelial cell proliferation in vitro.^[13] Concurrently in 1989, David W. Leung and colleagues, including Ferrara, isolated complementary DNA (cDNA) clones for both bovine and human VEGF from libraries derived from pituitary folliculostellate cells and HL60 leukemia cells, respectively.^[14] Sequence analysis revealed a precursor protein of approximately 232 amino acids for the human form, featuring a signal peptide for secretion and a domain structure with homology to the platelet-derived growth factor (PDGF) family, particularly in cysteine residues forming a cystine-knot motif essential for dimerization.^[14] The mitogenic activity on endothelial cells prompted the coining of the name "vascular endothelial growth factor" in this work, emphasizing its role as a secreted angiogenic mitogen.^[14] By 1991, Harold F. Dvorak's group connected VEGF to the earlier-described vascular permeability factor (VPF), demonstrating through purification and sequencing that VPF from tumor ascites fluid was identical to VEGF, with concentrated expression in tumor blood vessels supporting its in vivo angiogenic function. Early assays, including subcutaneous implantation in animal models, confirmed VEGF's ability to induce neovascularization, solidifying its identity as a key mediator of pathological angiogenesis. These milestones established VEGF as a distinct 45-50 kDa dimeric protein with potent endothelial-specific effects.

Structure

Protein Domains

Vascular endothelial growth factor (VEGF), exemplified by the prototypical VEGF-A, functions as a homodimeric glycoprotein, with each subunit consisting of disulfide-linked polypeptide chains typically spanning 121 to 165 amino acids in length across common isoforms. The dimer is covalently stabilized by two interchain disulfide bridges connecting Cys⁵¹ and Cys⁶⁰ between the monomers, a feature integral to its structural integrity and bioactivity. This architecture places VEGF-A within the cystine-knot growth factor superfamily, where the cystine-knot motif—encompassing key cysteine residues from positions approximately 26 to 104—facilitates both intrachain stabilization through disulfides at Cys²⁶-Cys⁶⁸, Cys⁵⁷-Cys¹⁰², and Cys⁶¹-Cys¹⁰⁴, and the overall dimerization process.^[15]^[16] Central to the protein's molecular architecture is the N-terminal α-helix, spanning residues 16 to 24, which forms part of the receptor-binding interface and contributes to the dimer's functional conformation. The core domain adopts a characteristic fold featuring a central antiparallel four-stranded β-sheet (strands β1: 27-34, β3: 51-58, β5: 73-83, β6: 89-99) augmented by an adjacent three-stranded sheet (β2: 46-49, β5, β6), resulting in an overall eight-stranded β-sheet arrangement that supports the cystine knot at one terminus. High-resolution insights into this structure were provided by X-ray crystallography of the receptor-binding domain (residues 8-109) at 1.93 Å in 1997, revealing the side-by-side antiparallel dimer orientation with a buried interface area of approximately 2695 Å². NMR studies from the same era further delineated the flexible N- and C-terminal extensions beyond the core domain.^[16]^[15] In longer VEGF-A variants, a distinct heparin-binding domain, encoded by exons 7 and 8 of the VEGFA gene, extends from the core structure (residues ~110-165) and enables electrostatic interactions with heparan sulfate proteoglycans in the extracellular matrix, thereby modulating bioavailability and localization. The solution structure of this domain, determined by NMR, highlights its positively charged surface residues critical for binding affinity. Post-translational modifications enhance VEGF-A's functionality, including N-linked glycosylation at Asn⁷⁴ (mature numbering), which influences stability and secretion, as well as proteolytic processing by enzymes such as plasmin and matrix metalloproteinases that cleave the C-terminal region to regulate matrix association and release of bioactive forms.^[17]^[18]^[19]

Gene and Variants

The human VEGFA gene is located on the short arm of chromosome 6 at position 6p21.1 and spans approximately 16 kb, consisting of eight exons and seven introns.^[20]^[21] The gene's genomic organization supports the production of multiple transcripts through alternative splicing, with exons 1–5 being common to all major isoforms, while exons 6, 7, and 8 contribute to structural and functional diversity.^[22] The promoter region of VEGFA contains hypoxia-responsive elements (HREs) that bind hypoxia-inducible factor 1-alpha (HIF-1α), enabling transcriptional activation under low-oxygen conditions to regulate angiogenesis.^[23] This HIF-1α-mediated mechanism is critical for inducible expression in response to hypoxia, as demonstrated in cellular and animal models where disruption of the HRE abolishes hypoxia-driven VEGFA upregulation.^[23] Several single nucleotide polymorphisms (SNPs) in the VEGFA gene influence transcription levels and are associated with disease susceptibility. For instance, the rs699947 (-2578C>A) SNP in the promoter region alters binding sites for transcription factors, leading to increased VEGFA expression and heightened risk for conditions such as breast cancer progression and cardiovascular diseases.^[24] Similarly, the rs2010963 (-634G>C) SNP in the 5' untranslated region affects mRNA stability and translation efficiency, correlating with elevated plasma VEGF-A levels and susceptibility to diabetic retinopathy and myocardial infarction.^[25]^[26] These variants demonstrate how common genetic changes can modulate VEGFA function in pathological angiogenesis. The VEGFA gene exhibits strong evolutionary conservation across mammals, with high sequence homology in coding regions and a preserved intron-exon structure that facilitates alternative splicing similar to that in rodents and primates.^[27] This conservation underscores the essential role of VEGF-A in vertebrate vascular development, as evidenced by orthologous genes in species from mice to humans sharing the eight-exon architecture.^[27] Rare mutations in VEGFA can significantly impair angiogenesis. For example, the p.Val258Ala variant (c.773T>C) disrupts protein secretion and receptor binding, leading to abnormal vascular development and associations with nonsyndromic cleft lip with or without cleft palate through defective angiogenic signaling.^[28]

VEGF Family and Isoforms

Family Members

The vascular endothelial growth factor (VEGF) family comprises five structurally related ligands in mammals: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). These proteins belong to the platelet-derived growth factor (PDGF)/VEGF superfamily, which arose through gene duplication events early in the evolution of multicellular organisms, with homologs present in invertebrates such as Drosophila and Caenorhabditis elegans for roles in cell migration and neurogenesis.^[27] All family members share a conserved cysteine-knot motif formed by eight cysteine residues, enabling homodimerization and heparin-binding capabilities that support their roles in vascular development.^[27] However, they exhibit distinct structural features, such as the presence of N- and C-terminal extensions in VEGF-C and VEGF-D, and variations in exon organization (eight exons in VEGF-A, seven in the others).^[29] VEGF-A serves as the prototypical member, primarily driving angiogenesis and vascular permeability during embryonic development and in response to hypoxia.^[27] VEGF-B contributes to endothelial maintenance and cardiac function, with expression predominantly in the myocardium and skeletal muscle, where it supports tissue protection and metabolic regulation.^[29] VEGF-C is essential for lymphangiogenesis, promoting the growth of lymphatic vessels.^[27] VEGF-D similarly facilitates lymphatic development and vascular expansion, often co-expressed with VEGF-C in lymphatic endothelium.^[29] PlGF, closely related to VEGF-A with about 53% amino acid identity in its VEGF homology domain, aids in trophoblast support and placental angiogenesis, with high expression in the placenta and ischemic tissues.^[27] Beyond mammals, VEGF family variants exist in non-mammalian contexts, including viral and reptilian forms derived from gene capture or duplication. VEGF-E, found in parapoxviruses such as the Orf virus, enhances angiogenesis to promote lesion formation and facilitate viral replication and immune modulation.^[27] Snake venom vascular endothelial growth factors (svVEGFs or VEGF-Fs), identified in species like Vipera ammodytes (vammin) and Trimeresurus flavoviridis, feature a conserved VEGF homology domain but highly variable C-terminal regions, enabling potent induction of vascular permeability and angiogenesis for prey immobilization.^[30]

Isoforms

The vascular endothelial growth factor A (VEGF-A) gene produces multiple protein isoforms through alternative splicing of its pre-mRNA, primarily involving exons 6, 7, and 8 out of a total of eight exons, resulting in variants such as VEGF-111, VEGF-121, VEGF-145, VEGF-165, VEGF-183, VEGF-189, and VEGF-206, with the numerical suffixes indicating the length in amino acids of the mature protein.^[31]^[32] These isoforms share a core structure but vary in the inclusion of heparin-binding domains encoded by exons 6 and 7, which determine their biochemical properties, such as solubility, extracellular matrix association, and spatiotemporal distribution during angiogenesis.^[33]^[34] Functional distinctions among VEGF-A isoforms arise from these structural variations, influencing their interactions with receptors and the extracellular matrix. VEGF-121, lacking exons 6 and 7, is a soluble, non-heparin-binding isoform that diffuses freely to exert diffuse paracrine effects on endothelial cells, promoting endothelial proliferation and migration without strong localization.^[34]^[35] In contrast, VEGF-165, the predominant isoform, includes exon 6 but excludes exon 7, providing moderate heparin binding for balanced solubility and matrix association, serving as the prototypical form in most physiological and pathological contexts.^[32]^[2] The more matrix-bound isoforms, such as VEGF-189 (including exons 6 and 7) and VEGF-206 (highly basic and strongly heparin-affine), remain predominantly sequestered in the extracellular matrix, enabling sustained, localized signaling that supports vessel maturation and stability rather than rapid sprouting.^[34]^[35] These isoform-specific activities contribute to nuanced regulation of angiogenesis, as demonstrated in experimental models. For example, in mice engineered to express only the VEGF-120 isoform (homologous to human VEGF-121), embryonic vascular development proceeds to term, but adults exhibit impaired myocardial angiogenesis, skeletal muscle capillary density, and ischemic cardiomyopathy, underscoring the non-redundant roles of longer isoforms in tissue-specific vessel formation.^[35] Similarly, isoform ratios influence vessel morphology; low concentrations of VEGF-121 or VEGF-165 promote elongated, thin vessels, whereas higher levels enhance vessel diameter and branching, with VEGF-165 showing greater potency in permeability induction.^[36] Isoforms of other VEGF family members, such as VEGF-C, are also generated by alternative splicing and post-translational processing, with full-length VEGF-C requiring proteolytic cleavage to fully activate VEGFR-3 and drive lymphangiogenesis, contrasting the primarily splicing-driven diversity in VEGF-A.^[37]^[2] Regulation of VEGF-A alternative splicing is mediated by serine/arginine-rich (SR) proteins, such as SRSF1 and SRSF3, which facilitate exon inclusion, and is modulated by environmental cues like hypoxia, which upregulates pro-angiogenic isoforms (e.g., VEGF-165) via stabilization of splicing factors and shifts in RNA-binding protein activity.^[22]^[38]^[31]

Receptors and Mechanism

Receptors

Vascular endothelial growth factor (VEGF) ligands primarily bind to three homologous receptor tyrosine kinases: VEGFR-1 (also known as Flt-1), VEGFR-2 (KDR or Flk-1), and VEGFR-3 (Flt-4). VEGFR-1 exhibits high affinity for VEGF-A, VEGF-B, and placental growth factor (PlGF), often functioning as a decoy receptor that sequesters these ligands to modulate their availability for other receptors. VEGFR-2 serves as the principal mediator of VEGF-A-induced signaling in angiogenesis, with lower affinity for VEGF-A but robust activation potential. VEGFR-3 preferentially binds VEGF-C and VEGF-D, playing a central role in lymphangiogenesis. These receptors share a conserved structural architecture typical of type III receptor tyrosine kinases, featuring an extracellular region with seven immunoglobulin-like domains (D1–D7) responsible for ligand binding, a single-span transmembrane helix, and an intracellular portion containing a split tyrosine kinase domain interrupted by a kinase insert sequence. Ligand binding primarily involves D2 and D3 domains, while D1, D4–D7 contribute to regulation and dimerization. The kinase inserts vary in length, influencing autophosphorylation and signaling efficiency.^[39]^[40] VEGFR-2 is predominantly expressed on vascular endothelial cells, with additional presence in hematopoietic progenitors and megakaryocytes. VEGFR-3 is mainly restricted to lymphatic endothelial cells, particularly during developmental and pathological lymphangiogenesis. VEGFR-1 shows broader distribution, including vascular endothelial cells, monocytes, macrophages, and trophoblasts. A naturally occurring soluble splice variant of VEGFR-1 (sVEGFR-1), lacking the transmembrane and cytoplasmic domains, functions as an endogenous inhibitor by binding and neutralizing circulating VEGF ligands.^[2] Neuropilins 1 and 2 (NRP-1 and NRP-2) act as non-enzymatic co-receptors that enhance the interaction between specific VEGF isoforms, such as VEGF-165, and VEGFR-2, thereby amplifying signaling on endothelial cells.^[3]

Signaling Pathways

Upon binding of vascular endothelial growth factor (VEGF) to its primary receptor, vascular endothelial growth factor receptor 2 (VEGFR-2), the receptor undergoes dimerization, leading to activation of its intracellular tyrosine kinase domain and subsequent autophosphorylation at specific tyrosine residues.^[2] Key phosphorylation sites include Y951 in the kinase insert region, which recruits Src family kinases, and Y1175 in the C-terminal tail, which binds phospholipase Cγ (PLCγ) to initiate downstream signaling.^[41]^[42] These events trigger a cascade of intracellular signals that promote endothelial cell responses essential for vascular development.^[43] The major signaling pathways activated by autophosphorylated VEGFR-2 include the PI3K/Akt pathway, which enhances endothelial cell survival and proliferation by inhibiting apoptosis through phosphorylation of Bad and activation of mTOR; the MAPK/ERK pathway, which drives cell migration via transcription factor activation and cytoskeletal remodeling; the PLCγ/PKC pathway, which increases vascular permeability by elevating intracellular calcium and activating protein kinase C isoforms; and the Src/FAK pathway, which regulates cell adhesion and motility through focal adhesion kinase phosphorylation and integrin activation.^[43]^[44] These pathways often converge to coordinate endothelial behaviors, with VEGFR-2 serving as the central mediator of VEGF's angiogenic effects.^[2] VEGFR-2 signaling exhibits cross-talk with integrins and cadherins, facilitating cytoskeletal changes critical for endothelial dynamics. For instance, Src activation at Y951 bridges VEGFR-2 to integrin signaling, promoting FAK-mediated actin reorganization, while VE-cadherin engagement modulates RhoA activity to balance tension at adherens junctions during VEGF-induced responses.^[45]^[46] Negative regulation occurs via phosphatases such as PTEN, which dephosphorylates PIP3 to attenuate PI3K/Akt signaling, and dual-specificity phosphatases (DUSPs), which dephosphorylate ERK to limit MAPK activation and prevent excessive proliferation.^[47]^[48] Signaling outcomes are dose-dependent, with low VEGF concentrations (e.g., 1-10 ng/mL) preferentially activating migration via sustained ERK signaling, while higher doses (e.g., >50 ng/mL) shift toward proliferation through amplified PI3K/Akt and MAPK pathways.^[49] This biphasic response allows precise tuning of endothelial functions in physiological contexts.^[50]

Expression and Regulation

Sites of Expression

Vascular endothelial growth factor (VEGF) is prominently expressed during embryonic development, particularly in the mesoderm and extra-embryonic endoderm, where it supports vasculogenesis and the formation of the cardiovascular system.^[2] High levels of VEGF mRNA are observed in the yolk sac, embryonic sites of vessel assembly, placenta, and developing kidney, correlating with the recruitment and maintenance of angiogenic cells and vessels.^[51]^[52] In the placenta, VEGF expression is associated with fetal and placental angiogenesis, ensuring proper vascular development.^[53] In adult tissues, VEGF exhibits low basal expression in organs such as the heart, lung, and brain, contributing to the maintenance of mature vasculature under normoxic conditions.^[54] Quantitative RT-PCR studies have detected constitutive VEGF mRNA in these tissues, with relative levels varying by organ; for instance, lung tissue shows detectable VEGF transcripts in normal human samples, though at lower abundance compared to developing structures.^[55] Expression is upregulated in specific physiological contexts, including healing wounds where VEGF promotes tissue repair, and in the corpus luteum during the ovarian cycle to support transient angiogenesis.^[56]^[57] VEGF is produced by diverse cell types under normal conditions, including endothelial cells, which express it for autocrine and paracrine effects in vascular homeostasis.^[54] Podocytes in the kidney glomeruli and tubular epithelia synthesize VEGF to regulate local vascular permeability and integrity.^[58] Macrophages constitutively produce VEGF, with mRNA detectable via RT-PCR, aiding in tissue remodeling and angiogenesis in response to environmental cues.^[59] Keratinocytes express VEGF-A, particularly in the skin, where it functions in an autocrine manner to support epidermal integrity and migration.^[60] Cell-specific expression patterns include pericytes, which produce cell-associated VEGF to stabilize adjacent endothelial cells in a juxtacrine or paracrine fashion, and vascular smooth muscle cells, where VEGF mRNA is present and responsive to angiogenic stimuli.^[61]^[62] Isoform preferences vary; for example, the VEGF-189 isoform, which binds strongly to the extracellular matrix, is expressed in pericytes and smooth muscle cells, potentially limiting its diffusion and enhancing local effects.^[63] Hypoxia can induce VEGF expression across these sites, amplifying production in response to low oxygen.^[64]

Regulatory Factors

Vascular endothelial growth factor (VEGF) expression is tightly regulated at multiple levels to ensure appropriate angiogenic responses. A primary environmental regulator is hypoxia, which induces VEGF transcription through the stabilization and activation of hypoxia-inducible factor-1α (HIF-1α). Under normoxic conditions, HIF-1α is hydroxylated by prolyl hydroxylase domain enzymes (PHDs) at specific proline residues, marking it for ubiquitination by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex and subsequent proteasomal degradation.^[65] In low oxygen environments, PHD activity is inhibited, preventing hydroxylation and allowing HIF-1α to accumulate, translocate to the nucleus, and dimerize with HIF-1β (ARNT). This heterodimer binds to hypoxia response elements (HREs) in the VEGF promoter, typically sequences like 5'-RCGTG-3', thereby upregulating VEGF gene transcription.^[65] This mechanism is particularly prominent in tissues experiencing ischemia, such as hypoxic tumors or developing embryos.^[65] Growth factors also play a key role in transcriptional upregulation of VEGF via specific promoter elements. Transforming growth factor-β (TGF-β) induces VEGF expression by activating Smad signaling pathways that enhance transcription, often in coordination with hypoxia-responsive elements.^[66] Similarly, platelet-derived growth factor (PDGF) stimulates VEGF production in fibroblasts and endothelial cells through activation of MAPK pathways, which phosphorylate and activate transcription factors binding to the VEGF promoter.^[67] The VEGF promoter contains binding sites for Sp1 and AP-2 transcription factors, which mediate these inductive effects; for instance, Sp1 sites facilitate PDGF- and TGF-β-driven transactivation by recruiting co-activators to the CpG-rich region upstream of the transcription start site.^[29]^[67] Post-transcriptional mechanisms further fine-tune VEGF levels, including microRNA (miRNA)-mediated suppression and control of mRNA stability. miR-126, for example, directly targets the 3' untranslated region (UTR) of VEGF mRNA, leading to its degradation or translational repression and thereby suppressing VEGF expression in contexts like lung cancer cells.^[68] VEGF mRNA stability is regulated by AU-rich elements (AREs) in its 3' UTR, which bind proteins such as tristetraprolin (TTP) and AUF1; these interactions promote deadenylation and decay, shortening the mRNA half-life under non-angiogenic conditions.^[69]^[70] Inhibitory signals counteract VEGF induction to prevent excessive angiogenesis. Tumor necrosis factor-α (TNF-α) downregulates VEGF expression in endothelial cells by activating NF-κB pathways that repress promoter activity, reducing transcription in inflammatory settings.^[71] Interferon-γ (IFN-γ) similarly inhibits VEGF by interfering with HIF-1α signaling and Sp1/Sp3 binding, leading to decreased mRNA levels and suppressed angiogenesis in immune-responsive tissues.^[72] At the protein level, VEGF stability is controlled by proteasomal degradation; ubiquitination targets intracellular VEGF for breakdown via the 26S proteasome, particularly when signaling is dysregulated.^[73] Autoregulatory feedback loops maintain VEGF homeostasis. VEGF itself promotes its own expression through an autocrine mechanism involving VEGFR-2 activation on producing cells, such as endothelial or tumor cells; ligand binding to VEGFR-2 triggers intracellular signaling that amplifies VEGF transcription, forming a feed-forward loop essential for sustained angiogenic drive.^[74]

Physiological Roles

Angiogenesis and Vasculogenesis

Vascular endothelial growth factor (VEGF), particularly VEGF-A, is indispensable for vasculogenesis, the process of de novo blood vessel formation from angioblasts during embryonic development. VEGF-A stimulates the differentiation of mesodermal precursors into endothelial progenitor cells, enabling the initial assembly of vascular networks.^[17] Inactivation of the VEGF-A gene in mice results in embryonic lethality, even in heterozygous embryos, due to profound defects in endothelial cell development and vascular structure formation. Similarly, targeted disruption of Flk-1 (also known as VEGFR-2), the primary receptor for VEGF-A, causes embryonic death around day 8.5-9.5 post-coitum, characterized by the absence of endothelial cells and failure to form blood islands, underscoring VEGF-A's critical signaling through this receptor for vasculogenic processes. Angiogenesis, the sprouting of new blood vessels from pre-existing vasculature, is predominantly orchestrated by VEGF-A in both development and adulthood. This process begins with the activation of endothelial cells by VEGF gradients, leading to the selection of tip cells that extend filopodia to sense and migrate toward the signal source. These tip cells guide sprout invasion into the extracellular matrix, facilitated by VEGF-induced activation of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which degrade basement membranes and interstitial matrix to enable endothelial invasion. Stalk cells behind the tip cells proliferate to elongate the sprout, while pericyte recruitment stabilizes the nascent structure. The angiogenic cascade driven by VEGF-A encompasses distinct stages: endothelial cell proliferation, primarily mediated by VEGFR-2 activation of the ERK/MAPK pathway; directed migration of tip cells via PI3K/Akt signaling for cytoskeletal reorganization and chemotaxis; and tube formation, involving VE-cadherin-mediated cell-cell adhesions that establish vascular lumens and integrity. In vitro models demonstrate that VEGF-A concentrations of 10-100 ng/ml optimally induce endothelial sprouting and network formation, with lower doses insufficient for robust response and higher doses potentially inhibitory due to receptor desensitization. In adult physiology, VEGF-A supports angiogenesis during wound healing, where it is upregulated in keratinocytes and macrophages to promote granulation tissue vascularization and tissue repair. It also drives cyclic angiogenesis in the ovarian corpus luteum, coordinating follicular rupture and luteal development through endothelial proliferation and vessel remodeling. The chick chorioallantoic membrane (CAM) assay exemplifies VEGF-A's angiogenic potency, where implantation of VEGF-A induces dose-dependent increases in vessel density and branching, providing a quantifiable in vivo model for studying vascular responses.^[75]

Additional Functions

Vascular endothelial growth factor A (VEGF-A) plays a critical role in regulating vascular permeability by inducing the formation of endothelial cell gaps, primarily through the activation of Src family kinases that phosphorylate vascular endothelial (VE)-cadherin, leading to disassembly of adherens junctions.^[76] This mechanism is essential for physiological processes such as tissue fluid exchange and wound healing, where controlled permeability facilitates nutrient delivery and immune cell extravasation.^[77] Beyond vascular functions, VEGF family members, particularly VEGF-B and VEGF-C, contribute to neurogenesis by promoting neuronal survival, migration, and differentiation in the adult brain. In the hippocampus, VEGF enhances the proliferation and migration of neural progenitor cells, supporting synaptic plasticity and memory formation through activation of VEGFR-2 and downstream signaling pathways like ERK and Akt.^[78] VEGF-C, acting via VEGFR-3, stimulates neural stem cell proliferation and migration,^[79] while VEGF-B supports neuronal protection against ischemia.^[80] In bone physiology, VEGF is involved in osteoclastogenesis by stimulating osteoclast precursor differentiation and activity, which is crucial for bone remodeling.^[81] During fracture healing, VEGF promotes endochondral ossification by enhancing chondrocyte hypertrophy and subsequent vascular invasion of the cartilage template, accelerating callus formation and mineralization.^[82] VEGF also influences hematopoiesis through VEGFR-1 expression on hematopoietic progenitor cells, where it supports their mobilization, proliferation, and differentiation into myeloid lineages under hypoxic conditions.^[83] In fertility, VEGF drives vascularization of ovarian follicles by inducing angiogenesis in the theca layer, ensuring adequate nutrient supply for oocyte maturation and corpus luteum development.^[84] Evidence from conditional knockout models underscores these non-vascular roles; for instance, studies demonstrate that VEGF acts directly on neural progenitors to regulate neurogenesis independently of its vascular effects,^[85] while bone-specific knockouts lead to disrupted osteoclast function and delayed fracture repair.^[86] Similarly, ovarian conditional knockouts demonstrate reduced follicular vascularization and fertility without global vascular abnormalities.^[87]

Clinical Significance

Pathological Involvement

Vascular endothelial growth factor (VEGF), primarily through its VEGF-A isoform, plays a central role in pathological angiogenesis by promoting excessive vascular proliferation and permeability when dysregulated. In cancer, VEGF-A overexpression drives tumor angiogenesis, enabling nutrient supply and tumor growth; for instance, elevated VEGF levels correlate with increased microvascular density and metastasis risk in colorectal cancer, where high serum VEGF concentrations are associated with advanced disease stages and poorer prognosis.^[88]^[89] This dysregulation exaggerates VEGF's physiological role in vascular development, leading to aberrant vessel formation that facilitates tumor invasion and dissemination.^[90] In ocular pathologies, VEGF contributes to neovascularization and vascular leakage in conditions such as diabetic retinopathy and wet age-related macular degeneration (AMD). In diabetic retinopathy, hypoxia-induced VEGF upregulation causes retinal neovascularization and breakdown of the blood-retinal barrier, resulting in edema and vision loss.^[91] Similarly, in wet AMD, increased VEGF expression promotes choroidal neovascularization, leading to subretinal fluid accumulation and photoreceptor damage; genetic associations, such as VEGF polymorphisms (e.g., rs833069), heighten AMD risk by enhancing VEGF production.^[92]^[93] Cardiovascular diseases involve both VEGF deficiency and excess in distinct contexts. In coronary artery disease, reduced VEGF expression impairs collateral vessel formation, contributing to myocardial ischemia and limited revascularization.^[94] Conversely, in atherosclerosis, excessive VEGF promotes plaque neovascularization, enhancing inflammation and instability, which increases rupture risk and acute events.^[95] Beyond these, VEGF dysregulation manifests in rheumatoid arthritis (RA), psoriasis, and preeclampsia. In RA, elevated synovial VEGF drives pannus angiogenesis, sustaining chronic inflammation and joint destruction; serum VEGF levels positively correlate with disease activity scores.^[96]^[97] In psoriasis, VEGF overexpression induces dermal angiogenesis, exacerbating plaque formation and epidermal hyperplasia through increased vascular permeability.^[98] In preeclampsia, placental VEGF deficiency, often due to upregulated soluble fms-like tyrosine kinase-1 (sFlt-1) that sequesters VEGF, leads to endothelial dysfunction and insufficient uteroplacental perfusion.^[99]^[100] Overall, serum VEGF levels serve as a biomarker across these conditions, with elevations in inflammatory and neoplastic diseases and reductions in vasculogenic insufficiencies, while single nucleotide polymorphisms (SNPs) in the VEGF gene, such as those in AMD, underscore genetic predispositions to pathology.^[101]

Therapeutic Applications

Vascular endothelial growth factor (VEGF) targeted therapies primarily focus on inhibiting VEGF signaling to suppress pathological angiogenesis in conditions such as cancer and ocular diseases. Anti-VEGF monoclonal antibodies represent a cornerstone of these interventions. Bevacizumab (Avastin), a humanized monoclonal antibody that binds all isoforms of VEGF-A, was approved by the FDA in 2004 as a first-line treatment for metastatic colorectal cancer in combination with fluorouracil-based chemotherapy, demonstrating improved overall survival in pivotal trials.^[102] Ranibizumab (Lucentis), a recombinant humanized monoclonal antibody fragment targeting VEGF-A, received FDA approval in 2006 for intravitreal treatment of neovascular (wet) age-related macular degeneration (AMD), showing significant visual acuity improvements in phase III studies.^[103] Small-molecule tyrosine kinase inhibitors targeting VEGF receptors (VEGFRs) offer oral alternatives for systemic use, particularly in oncology. Sorafenib, a multikinase inhibitor primarily targeting VEGFR-2 and VEGFR-3, was approved for advanced renal cell carcinoma and hepatocellular carcinoma, where it extends progression-free survival by disrupting VEGF-mediated tumor angiogenesis.^[104] Axitinib, a potent selective inhibitor of VEGFR-1, -2, and -3, demonstrated superior progression-free survival compared to sorafenib in second-line treatment of advanced renal cell carcinoma in the phase III AXIS trial.^[105] In ophthalmology, VEGF traps and bispecific agents have advanced intravitreal therapies for retinal disorders. Aflibercept (Eylea), a fusion protein that acts as a soluble VEGF receptor trap binding VEGF-A and placental growth factor (PlGF), was approved by the FDA in 2011 for wet AMD and later for diabetic macular edema (DME), offering dosing intervals up to every 8 weeks after initial loading based on VIEW trials showing noninferiority to ranibizumab.^[106] Faricimab (Vabysmo), the first bispecific antibody inhibiting both VEGF-A and angiopoietin-2 (Ang-2), gained FDA approval in 2022 for wet AMD and DME, with phase III TENAYA and LUCERNE trials indicating extended durability and reduced injection frequency compared to aflibercept.^[107] Pro-angiogenic approaches using VEGF stimulation have been explored for ischemic diseases, though with limited success. In the 2000s, VEGF gene therapy trials, such as the NORTHERN trial using adenovirus-delivered VEGF for refractory angina, aimed to promote therapeutic angiogenesis in coronary artery disease but failed to improve myocardial perfusion, highlighting challenges in vector delivery and efficacy.^[108] Recent advances from 2023 to 2025 emphasize sustained-release formulations and combination strategies to enhance efficacy and patient compliance. Brolucizumab, a single-chain antibody fragment against VEGF-A, demonstrated noninferiority to aflibercept in best-corrected visual acuity improvement and superiority in central subfield thickness reduction in the phase 3 KINGFISHER trial for DME in 2024-2025 analyses, regardless of prior anti-VEGF exposure.^[109] In non-small cell lung cancer (NSCLC), combinations of anti-VEGF agents like bevacizumab with immune checkpoint inhibitors (ICIs) have been investigated.^[110] Conbercept, a VEGF trap similar to aflibercept, showed comparable efficacy in DME treatment in a 2025 systematic review, with similar anatomical outcomes and potential for reduced treatment burden in Asian populations.^[111] Despite these successes, VEGF-targeted therapies face challenges including resistance mechanisms and adverse effects. Tumor resistance often arises from alternative angiogenic pathways or VEGF-independent signaling, necessitating combination regimens.^[112] Common side effects include hypertension, occurring in 30-80% of patients due to VEGF inhibition-induced endothelial dysfunction and microvascular rarefaction, requiring proactive blood pressure monitoring and management.^[113]

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