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Neovascularization

Neovascularization refers to the formation of new blood vessels, regardless of their size or type, often driven by physiological needs or pathological conditions. This process primarily involves angiogenesis, the sprouting or splitting of new vessels from pre-existing vasculature, and vasculogenesis, the de novo assembly of endothelial cells into primitive vascular networks—primarily during embryonic development but also possible in adults.^[1]^[2] In physiological contexts, neovascularization supports tissue growth and repair, such as during embryonic development, wound healing, exercise-induced muscle adaptation, or adipose tissue expansion in response to weight gain. For instance, it ensures that no tissue is more than a few hundred micrometers from a capillary, maintaining oxygen and nutrient delivery under metabolic demands.^[1] Key regulators include vascular endothelial growth factor (VEGF), which promotes endothelial cell proliferation and migration, alongside hemodynamic and hypoxic signals that balance angiogenic and anti-angiogenic factors.^[1]^[2] Pathologically, neovascularization contributes to numerous diseases by enabling abnormal vessel growth that exacerbates tissue damage. In cancer, it sustains tumor progression by providing essential nutrients and oxygen, as hypothesized by Judah Folkman in 1971, leading to therapeutic strategies like anti-VEGF inhibitors.^[1] Ocular disorders, including diabetic retinopathy, age-related macular degeneration, and corneal neovascularization, feature aberrant vessel invasion that causes vision loss through hemorrhage or edema.^[2] Similarly, in atherosclerosis, plaque neovascularization heightens vulnerability to rupture and inflammation, while in rheumatoid arthritis, it fuels chronic joint destruction.^[2] These roles underscore neovascularization's dual nature, where it is harnessed for treatments in ischemic conditions but targeted for inhibition in proliferative diseases.^[1]

Definition and Overview

Definition

Neovascularization refers to the formation of new blood vessels, a term derived from the prefix "neo-" (meaning new) combined with "vascularization" (the process of developing blood vessels), with its earliest documented use appearing in medical literature in 1952.^[3] The underlying biological process of generating functional vascular networks has been studied extensively since the early 20th century, particularly in the context of embryonic development, where systematic descriptions of vessel morphogenesis were pioneered by researchers like Florence Sabin through histological analyses of avian and mammalian embryos.^[4] At its core, neovascularization involves the de novo creation or adaptive remodeling of blood vessels to meet tissue demands for oxygen and nutrients in adult organisms. This occurs through the differentiation, migration, proliferation, and assembly of endothelial cells or their precursors into capillary-like tubes, often initiated by environmental cues such as hypoxia, which stabilizes hypoxia-inducible factors to upregulate angiogenic growth factors, alongside inflammatory mediators that recruit supporting cells.^[1]^[5] Vascular endothelial growth factor (VEGF) serves as a primary stimulator in this orchestration.^[6] Key cellular and structural elements include endothelial cells, which form the luminal lining and respond directly to signaling cues; pericytes, which envelop vessels to stabilize them, regulate blood flow, and prevent leakage; and the extracellular matrix, a dynamic network of proteins like collagen and laminin that provides mechanical support, guides cell adhesion via integrins, and modulates growth factor bioavailability during vessel assembly and maturation.^[7]^[8] Although neovascularization is sometimes used broadly to describe any new vessel growth, it is conceptually distinct from related processes: vasculogenesis entails the initial in situ differentiation of angioblasts (endothelial precursors) into primitive vascular plexuses, primarily during embryogenesis; angiogenesis involves the sprouting, branching, or splitting of capillaries from established vessels in response to local gradients; and arteriogenesis focuses on the shear stress-induced enlargement and maturation of preexisting arterial collaterals into functional conduits.

Physiological vs. Pathological Neovascularization

Neovascularization serves essential functions in normal physiology, where it is tightly regulated to support tissue development and repair in adults, but becomes detrimental when dysregulated in disease states. In physiological contexts, triggers such as transient hypoxia during wound healing activate hypoxia-inducible factor-1α (HIF-1α), which upregulates vascular endothelial growth factor (VEGF) and other pro-angiogenic factors to promote vessel formation.^[9] This process is balanced by endogenous inhibitors like thrombospondin-1 (TSP-1), which suppresses endothelial cell proliferation, migration, and survival through interactions with CD36 and CD47 receptors, ensuring controlled vascular expansion.^[10] As a result, physiological neovascularization yields stable, organized vasculature with proper pericyte coverage and low permeability, facilitating efficient oxygen delivery and tissue homeostasis.^[11] In contrast, pathological neovascularization arises from chronic or severe triggers, including prolonged tumor hypoxia, ischemia in ischemic diseases, and sustained inflammation, which lead to excessive HIF-1α stabilization and unchecked VEGF production.^[9] Chronic inflammation, for instance, recruits leukocytes that release pro-angiogenic chemokines, amplifying vessel sprouting in an uncontrolled manner, while tumor hypoxia induces an "angiogenic switch" favoring rapid but aberrant growth.^[11] Ischemia in non-healing wounds or vascular occlusions similarly drives dysregulated responses, often without adequate inhibitory counterbalance from factors like TSP-1.^[10] Consequently, pathological vessels are fragile, tortuous, and highly permeable due to incomplete pericyte recruitment and disrupted endothelial junctions, promoting hemorrhage, edema, and tumor metastasis.^[11] In pathology, particularly cancer, tumors hijack the angiogenic program—either by inducing new vessels or co-opting existing ones—to sustain uncontrolled proliferation.^[12] This transforms a beneficial process into one that exacerbates disease progression, underscoring the fine line between regulated adaptation and pathological exploitation.

Mechanisms of Neovascularization

Vasculogenesis

Vasculogenesis refers to the de novo formation of the initial vascular network during embryonic development, where mesodermal precursor cells differentiate into endothelial progenitor cells, known as angioblasts, which subsequently assemble into primitive vascular plexuses.^[13] This process begins with the commitment of lateral plate mesoderm to the endothelial lineage, followed by the migration, proliferation, and coalescence of angioblasts to form cord-like structures that eventually develop lumens and connect into a functional plexus.^[14] Unlike later vascular expansion, vasculogenesis establishes the foundational architecture of the circulatory system without reliance on pre-existing vessels.^[15] The modern understanding of vasculogenesis as an in situ process emerged in the late 1980s through pioneering studies using quail-chick chimera models, which demonstrated that endothelial cells arise locally from mesodermal precursors rather than solely migrating from extraembryonic sites.^[16] In these experiments, interspecific grafts revealed that somitic and splanchnopleural mesoderm in the avian embryo generates endothelial cells on site, forming blood islands and vascular tubes independently in different territories.^[17] This work, building on earlier histological observations, solidified vasculogenesis as a distinct mechanism of vessel origination in the 1990s, distinguishing it from migratory contributions.^[18] Central to vasculogenesis is the hemangioblast, a bipotent precursor cell derived from mesoderm that gives rise to both endothelial and hematopoietic lineages, as evidenced by clonal analyses and marker expression in avian and murine models.^[19] Key molecular regulators include vascular endothelial growth factor (VEGF), which promotes angioblast differentiation and survival via its receptors VEGFR-1 and VEGFR-2; fibroblast growth factor-2 (FGF-2), which induces mesodermal commitment to the endothelial fate and supports proliferation; and angiopoietins, particularly Ang-1, which stabilize nascent vessels through Tie-2 receptor signaling in coordination with VEGF.^[20] These factors act in a spatiotemporal cascade, with VEGF and FGF-2 initiating hemangioblast specification and angiopoietins aiding plexus maturation.^[21] In vitro models of vasculogenesis have been instrumental in dissecting these processes, particularly through the differentiation of embryonic stem (ES) cells into embryoid bodies, which recapitulate blood island formation and vascular channel development.^[22] When murine ES cells aggregate into cystic embryoid bodies, they spontaneously generate endothelial cells expressing markers like PECAM-1 and Flk-1, assembling into tube-like structures in a VEGF-dependent manner, mirroring embryonic vasculogenesis.^[23] These systems allow manipulation of signaling pathways, confirming the roles of FGF-2 and angiopoietins in enhancing network complexity without external scaffolds.^[24]

Angiogenesis

Angiogenesis is the process by which new blood vessels form from pre-existing vasculature through sprouting and branching, enabling tissue perfusion and growth in both physiological and pathological contexts.^[25] This highly regulated mechanism involves the coordinated activation, migration, and proliferation of endothelial cells, primarily driven by angiogenic signals in response to hypoxia or injury. Unlike de novo vessel formation, angiogenesis remodels mature vessels to expand the microvascular network.^[26] The process begins with the degradation of the extracellular matrix (ECM) surrounding existing vessels, facilitated by matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9, which are secreted by endothelial cells and pericytes to create pathways for sprout invasion.^[27] Specialized endothelial tip cells then emerge at the sprout front, extending filopodia—actin-rich protrusions that sense gradients of angiogenic factors like vascular endothelial growth factor (VEGF)—to guide directional migration.^[28] Trailing stalk cells proliferate to elongate the sprout, driven by VEGF signaling, while subsequent lumen formation occurs through endothelial cell rearrangement and vacuole fusion, establishing a patent vessel tube.^[29] Pericytes and smooth muscle cells later associate with the nascent vessel to promote maturation and stability.^[25] Key stimulators of angiogenesis include VEGF-A, which binds to its primary receptor VEGFR-2 on endothelial cells, activating downstream PI3K/Akt pathways that enhance cell survival, proliferation, and migration.^[30] Angiopoietin-1 (Ang-1), acting via the Tie2 receptor, complements VEGF by recruiting mural cells and stabilizing vessel walls, preventing leakage and supporting long-term functionality.^[31] Inhibitors such as endostatin and angiostatin, derived from collagen XVIII and plasminogen respectively, counteract these effects by suppressing endothelial proliferation and migration, often through interference with integrin signaling.^[32] Additionally, Notch signaling mediates lateral inhibition between tip and stalk cells, restricting excessive branching and ensuring orderly sprout patterning via Delta-like 4 (Dll4) ligands.00043-4) Vessel density resulting from angiogenesis is quantitatively assessed using microvessel density (MVD), a histological method that counts CD31- or von Willebrand factor-positive endothelial structures in tumor or tissue sections to gauge angiogenic activity and correlate it with disease progression.^[33] High MVD often indicates robust neovascularization, providing a prognostic marker in contexts like cancer.^[33]

Arteriogenesis

Arteriogenesis refers to the adaptive growth and remodeling of pre-existing arterioles into larger collateral arteries, primarily in response to hemodynamic forces such as increased fluid shear stress following vascular occlusion.^[34] This process enhances conductance vessel function to bypass obstructions and restore blood flow, occurring predominantly in non-ischemic regions where collateral vessels experience elevated tangential forces.^[35] Unlike other forms of vascular adaptation, arteriogenesis involves structural enlargement, with collateral arteries potentially increasing in diameter by up to 20-fold through coordinated cellular and molecular events.^[36] The process begins with endothelial cell activation by shear stress, leading to the expression of adhesion molecules and chemokines that facilitate monocyte recruitment into the vessel wall.^[34] Recruited monocytes differentiate into macrophages, which release proteases to degrade the extracellular matrix (ECM) and promote smooth muscle cell (SMC) dedifferentiation and proliferation, enabling vessel wall thickening and lumen expansion.^[35] ECM remodeling further supports this growth through the deposition of new collagen and elastin, driven by matrix metalloproteinases (MMPs) from macrophages and SMCs, resulting in a more robust arterial structure capable of withstanding higher pressures.^[36] Key regulators include monocyte chemoattractant protein-1 (MCP-1), which mediates monocyte chemotaxis via the CCR2 receptor to initiate inflammatory infiltration.^[34] Platelet-derived growth factor-BB (PDGF-BB) promotes pericyte and SMC recruitment for vessel stabilization, while basic fibroblast growth factor (bFGF) stimulates endothelial and SMC proliferation to drive outward remodeling.^[35] These factors act synergistically under shear stress to amplify arteriogenic responses. Arteriogenesis differs from angiogenesis by targeting pre-existing conductance vessels rather than forming new capillaries, with success often measured by the collateral flow index, which quantifies improved arterial perfusion independent of capillary density.^[36] Although both can be triggered by ischemic conditions, arteriogenesis emphasizes flow-mediated adaptation over hypoxia-driven sprouting.^[34] Experimental models, such as hindlimb ischemia induced by femoral artery ligation in mice, demonstrate flow-dependent collateral artery growth, where shear stress in upstream arterioles leads to partial restoration of perfusion within weeks through monocyte-dependent mechanisms.^[35] In these models, genetic ablation of MCP-1 impairs collateral development, underscoring its essential role.^[36]

Physiological Roles

Embryonic and Developmental Vasculogenesis

Vasculogenesis, the de novo formation of blood vessels from endothelial progenitor cells known as angioblasts, initiates during early embryogenesis to establish the primary vascular network. In humans, this process begins around week 3 of gestation, coinciding with gastrulation, when mesodermal cells in the extraembryonic yolk sac differentiate into hemangioblasts—bipotent precursors capable of giving rise to both endothelial and hematopoietic lineages. These hemangioblasts aggregate to form blood islands, which develop into the initial vascular structures, including the yolk sac vasculature and the primitive aortic arches that will contribute to the great vessels of the circulatory system.^[19]^[37] Spatially, embryonic vasculogenesis exhibits precise patterning driven by mesodermal origins and migratory cues. The paired dorsal aortae, which form the central axial vessels, primarily arise from angioblasts in the splanchnic lateral plate mesoderm, with additional contributions from the paraxial mesoderm, particularly the dermomyotome, where endothelial precursors delaminate and migrate to incorporate into the aortic endothelium. Intersomitic vessels, which supply the developing somites, emerge via vasculogenesis from angioblasts in the segmental plate—an unsegmented region of the paraxial mesoderm—before transitioning to sprouting patterns along the trunk. This organized spatial assembly ensures efficient coverage of the embryo, with the yolk sac vessels facilitating early nutrient exchange and the intraembryonic networks supporting organogenesis.^[38]^[39]^[40] Genetic regulation orchestrates hemangioblast specification and vascular tube formation through key transcription factors. The TAL1/SCL factor is indispensable for committing mesodermal progenitors to the hemangioblast lineage, activating downstream genes like FLK1 and promoting endothelial differentiation; its absence in model organisms results in complete failure of vasculogenesis and embryonic lethality due to lack of blood vessels. Mutations or disruptions in TAL1/SCL and related pathways, such as those involving GATA2 or ETS factors, are associated with congenital vascular malformations, including hypoplastic vessels and disorganized networks observed in developmental syndromes. Following primary vasculogenesis, the process largely gives way to angiogenesis for vascular expansion, though remnants persist postnatally.^[41]^[42] In adults, de novo vasculogenesis is rare and confined to specific contexts, such as reactivation within stem cell niches like the bone marrow, where endothelial progenitor cells (EPCs) derived from hematopoietic stem cells contribute to vessel formation under regenerative demands. These postnatal EPCs mirror embryonic hemangioblasts in function, integrating into existing vasculature or forming new segments in response to ischemic or hypoxic signals, highlighting a conserved mechanism from development.^[43]^[44]

Wound Healing and Tissue Repair

Neovascularization plays a critical role in the proliferative phase of wound healing, which typically spans days 4 to 21 post-injury, where it facilitates the formation of granulation tissue through angiogenesis.^[45] During this phase, endothelial cells proliferate and migrate to form new capillaries, providing essential oxygen and nutrients to support tissue regeneration and re-epithelialization.^[46] The process begins with the degradation of the provisional fibrin matrix by proteases, allowing endothelial sprouts to invade and organize into functional vessels within the granulation tissue.^[47] Key regulators of this neovascularization include hypoxia-induced vascular endothelial growth factor (VEGF) secreted by macrophages, which promotes endothelial cell proliferation, migration, and tube formation in the oxygen-deprived wound bed.^[48] Transforming growth factor-beta (TGF-β), released by various cells including platelets and fibroblasts, aids in matrix integration by enhancing extracellular matrix production and stabilizing newly formed vessels with pericytes and smooth muscle cells.^[49] As healing progresses into the remodeling phase, excess vessels regress through endothelial cell apoptosis, restoring a balanced vascular network and preventing chronic inflammation.^[50] Clinically, impaired neovascularization contributes to delayed wound closure in diabetic patients, often due to diminished VEGF responsiveness and hyperglycemia-induced endothelial dysfunction.^[51] Conversely, excessive neovascularization can lead to hypertrophic scarring in keloids, where persistent angiogenic signaling sustains abnormal tissue growth.^[52] Experimental models, such as the rabbit ear chamber assay, have been instrumental in quantifying vessel ingrowth rates.^[53] Additionally, bone marrow-derived endothelial progenitor cells contribute vasculogenesis-like processes to support this repair.^[54]

Other Physiological Contexts

Neovascularization also supports adaptation in skeletal muscle during endurance exercise training, where increased capillary density enhances oxygen delivery and metabolic efficiency. This angiogenesis is driven by shear stress from elevated blood flow and hypoxic signals, leading to proliferation of endothelial cells and improved endurance capacity, as observed in human studies showing up to 20-30% increases in capillary-to-fiber ratios after prolonged training.^[55] In adipose tissue expansion, such as during weight gain, neovascularization is essential for supplying nutrients to growing adipocytes, preventing hypoxia and fibrosis. Angiogenic factors like VEGF promote vessel sprouting within the expanding fat pads, with disruptions linked to unhealthy obesity phenotypes characterized by inflammation and metabolic dysfunction.^[56]

Pathological Conditions

Ocular Neovascularization Disorders

Ocular neovascularization disorders encompass a range of conditions characterized by the abnormal growth of blood vessels in the retina, choroid, or iris, primarily driven by retinal ischemia and hypoxia. In diabetic retinopathy (DR), chronic hyperglycemia leads to retinal capillary occlusion and ischemia, which upregulates vascular endothelial growth factor (VEGF) expression in retinal glial cells, promoting neovascularization.^[57] Similarly, in retinopathy of prematurity (ROP), hyperoxia-induced vaso-obliteration followed by relative hypoxia in premature infants triggers VEGF release, leading to aberrant vessel proliferation.^[58] These processes primarily involve angiogenesis, where new vessels sprout from existing capillaries in response to hypoxic signals.^[6] The clinical manifestations of these disorders often result in significant vision impairment through several mechanisms. Neovascular vessels are fragile and prone to leakage, causing macular edema that distorts central vision.^[59] More severe complications include vitreous hemorrhage, where blood from ruptured vessels obscures the visual axis, and tractional retinal detachment due to fibrovascular proliferation pulling on the retina.^[60] These features collectively contribute to progressive vision loss, with potential for sudden and profound deficits if untreated.^[61] Diagnosis relies on advanced imaging modalities to visualize and characterize neovascular activity. Fluorescein angiography (FA) is a cornerstone technique, revealing hyperfluorescent leakage patterns from abnormal vessels and areas of non-perfusion indicative of ischemia.^[62] Optical coherence tomography (OCT), including OCT angiography (OCTA), provides high-resolution cross-sectional images and non-invasive vessel quantification, detecting neovascular membranes and associated edema without dye injection.^[63] These tools enable early identification and monitoring of disease progression. Epidemiologically, proliferative DR, a key neovascular form, affects approximately 3.5% of diabetic adults in the United States as of 2021, with vision-threatening diabetic retinopathy (including neovascular complications) impacting 5.06% of the diabetic population.^[64]^[65] The incidence of PDR has declined by nearly 300% since 2002, but overall DR cases continue to rise with increasing diabetes prevalence, estimated at around 10 million affected individuals in the US by 2025 amid aging populations and urbanization, with projections indicating a substantial global burden through the 2020s.^[66]^[67]

Cancer-Associated Neovascularization

Cancer-associated neovascularization refers to the process by which tumors stimulate the formation of new blood vessels to support their growth and progression. This phenomenon was first hypothesized by Judah Folkman in 1971, who proposed that tumor expansion is limited by the need for angiogenesis and that inhibiting this process could serve as a therapeutic strategy. Folkman's seminal work laid the foundation for understanding tumors as "wounds that do not heal," highlighting the dependency of solid tumors on neovascularization for nutrient supply and oxygen delivery beyond a microscopic size of approximately 1-2 mm³.^[68] A pivotal event in this process is the angiogenic switch, where the balance shifts from an avascular, dormant state to one dominated by pro-angiogenic signals that exceed anti-angiogenic inhibitors. This switch is often triggered by oncogenes such as mutant RAS, which upregulate the expression of key pro-angiogenic factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).^[69] For instance, oncogenic H-RAS stimulates tumor angiogenesis through both autocrine VEGF production in tumor cells and paracrine bFGF secretion from stromal cells, enabling rapid vessel formation and tumor expansion.^[70] The resulting imbalance promotes endothelial cell proliferation, migration, and tube formation, transforming the tumor from a preclinical, non-invasive lesion into a malignant one capable of sustained growth.^[71] Within the tumor microenvironment, hypoxic conditions in the expanding tumor core play a central role in driving neovascularization. Hypoxia-inducible factor-1α (HIF-1α), stabilized under low oxygen levels, transactivates genes encoding pro-angiogenic molecules like VEGF, further amplifying vessel recruitment.^[72] Additionally, hypoxic tumors secrete stromal cell-derived factor-1 (SDF-1), which mobilizes endothelial progenitor cells (EPCs) from the bone marrow to incorporate into nascent vessels, enhancing neovascularization and tumor perfusion.^[73] This recruitment of EPCs, often CD45+ myeloid cells, integrates into the tumor vasculature, supporting its immaturity and leakiness, which facilitates immune evasion and nutrient delivery.^[74] Clinically, cancer-associated neovascularization enables metastasis by providing a vascular route for tumor cell dissemination and is associated with adverse outcomes. High microvessel density (MVD), a histological marker of angiogenesis assessed via CD34 or CD105 staining, correlates with poor prognosis in various cancers; for example, elevated MVD in breast cancer predicts shorter disease-free survival and increased metastatic risk.^[33] Similarly, in colon cancer, high intratumoral MVD is linked to reduced overall survival, particularly in advanced stages, underscoring its role as an independent prognostic indicator.^[75] These vessels not only sustain primary tumor growth but also create a permissive niche for circulating tumor cells to extravasate and colonize distant sites, exacerbating disease progression.^[76]

Cardiovascular Ischemic Diseases

In ischemic heart disease, neovascularization primarily manifests as collateral arteriogenesis, which is triggered by increased tangential fluid shear stress on endothelial cells following myocardial infarction (MI). This process enlarges pre-existing arterioles into functional collateral vessels, providing alternative blood flow to ischemic myocardium and reducing infarct size.^[77] However, arteriogenesis is often impaired in clinical settings, serving as an adaptive response to restore perfusion but limited by patient factors such as advanced age and comorbidities like diabetes, which reduce endothelial progenitor cell (EPC) recruitment and nitric oxide bioavailability.^[78]^[79] In peripheral artery disease (PAD), neovascularization through angiogenesis and arteriogenesis represents an adaptive mechanism to bypass occlusions in lower limb arteries, potentially alleviating intermittent claudication. Pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), hold therapeutic promise by stimulating capillary sprouting and collateral maturation to enhance limb perfusion.^[80] Yet, this response can become maladaptive, as excessive VEGF-induced vessel permeability increases the risk of hemorrhage and edema, complicating treatment in patients with critical limb ischemia.^[81] Key regulators modulate these processes; adipokines like adiponectin enhance EPC mobilization from bone marrow, promoting their incorporation into ischemic neovessels and improving post-ischemic recovery.^[82] Similarly, statins augment arteriogenesis by upregulating endothelial nitric oxide synthase (eNOS) activity, which supports endothelial cell survival and shear stress-mediated vessel remodeling without directly affecting cholesterol levels in this context.^[83] Recent advances in the 2020s, including follow-up analyses of VEGF gene therapy trials for intermittent claudication, demonstrate mixed outcomes, with some improvements in ankle-brachial index and walking distance but inconsistent reductions in amputation rates or sustained perfusion benefits.^[84] These findings highlight the need for optimized delivery methods to balance adaptive neovascularization against maladaptive vascular instability.

Therapeutic Strategies

Anti-Neovascularization Therapies

Anti-neovascularization therapies primarily target the vascular endothelial growth factor (VEGF) pathway, a key driver of pathological angiogenesis, by blocking VEGF signaling to inhibit excessive vessel formation in diseases like cancer and ocular disorders. Monoclonal antibodies such as bevacizumab (Avastin), the first FDA-approved anti-VEGF agent in 2004, directly bind to VEGF-A isoforms, preventing their interaction with VEGF receptors (VEGFRs) on endothelial cells and thereby suppressing endothelial proliferation, migration, and survival. This mechanism has been foundational, as VEGF-A is the predominant isoform promoting neovascularization in pathological contexts. In oncology, bevacizumab is commonly used in combination regimens to enhance efficacy against solid tumors by normalizing tumor vasculature and improving drug delivery. For instance, in metastatic colorectal cancer, bevacizumab combined with fluorouracil-based chemotherapy extended median overall survival by 4.7 months (from 15.6 to 20.3 months) in the pivotal AVF2107g trial, establishing its role in first-line therapy.^[85] Similarly, in ophthalmology, intravitreal injections of ranibizumab (Lucentis), a Fab fragment derived from the same parent antibody as bevacizumab and FDA-approved in 2006, bind VEGF-A with high affinity to treat neovascular age-related macular degeneration (wet AMD), reducing vascular leakage and stabilizing or improving visual acuity (losing fewer than 15 letters) in about 94.5% of patients, with approximately 34.7% gaining 15 or more letters, over two years.^[86] These applications highlight the therapy's specificity for ocular neovascularization, where localized delivery minimizes systemic exposure. Despite their success, anti-VEGF therapies face challenges including acquired resistance, often mediated by upregulation of alternative angiogenic pathways such as fibroblast growth factor (FGF) signaling, which can compensate for VEGF inhibition and sustain tumor progression. Additionally, common side effects like hypertension, proteinuria, and increased risk of arterial thromboembolism arise from systemic VEGF blockade, affecting up to 20-30% of patients on bevacizumab and necessitating careful monitoring. Emerging strategies address these limitations through multi-kinase inhibitors that target multiple receptors involved in neovascularization. Sunitinib (Sutent), approved by the FDA in 2006 for advanced renal cell carcinoma, inhibits VEGFR-1/2/3, PDGFR-β, and other kinases, achieving objective response rates of approximately 7% but clinical benefit rates (including stable disease) of around 53% in gastrointestinal stromal tumors resistant to prior therapies by broadly disrupting angiogenic signaling.^[87] These agents offer a complementary approach, potentially overcoming single-pathway resistance, though they introduce additional toxicities like hand-foot syndrome.

Pro-Neovascularization Therapies

Pro-neovascularization therapies aim to stimulate the formation of new blood vessels in ischemic tissues, such as those affected by cardiovascular diseases, to improve perfusion and promote tissue repair. These approaches primarily target the delivery of angiogenic factors like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to enhance neovascularization in conditions where natural revascularization is insufficient. Unlike anti-angiogenic strategies, these therapies seek to harness physiological vessel growth mechanisms for therapeutic benefit in regenerative contexts.^[88] Gene therapy represents a key approach, involving the intramuscular or epicardial injection of plasmids encoding pro-angiogenic factors to induce local expression. For instance, the pCMV-VEGF165 plasmid (Neovasculgen), which carries the VEGF-165 gene, has been used to stimulate angiogenesis in ischemic diseases through direct plasmid injection, demonstrating efficacy in preclinical and early clinical models by increasing capillary density. Similarly, NV1FGF, a plasmid-based therapy encoding FGF-1, has been administered via intramuscular injection in patients with critical limb ischemia, showing improved limb perfusion and reduced amputation rates in phase II trials, although a subsequent phase III trial (TAMARIS) did not confirm the reduction in major amputation rates as its primary endpoint.^[89]^[90]^[91]^[92] Protein delivery methods complement gene therapy by providing direct administration of recombinant angiogenic factors; recombinant FGF-1, for example, has been tested in preclinical rabbit models of hindlimb ischemia, where daily intramuscular injections led to significant improvements in blood flow and collateral vessel formation.^[89]^[90]^[91] In applications for refractory angina, adenoviral vector-based therapies like AdVEGF-D have shown promise in clinical trials during the 2010s and beyond. The phase I KAT301 trial demonstrated the safety and feasibility of intramyocardial AdVEGF-D injection, resulting in improved exercise tolerance and reduced angina episodes in patients with no-option refractory angina, with long-term follow-up confirming sustained benefits up to five years post-treatment. The more recent EXACT phase II trial using XC001 (AdVEGFXC1), an adenoviral VEGF construct, reported enhancements in exercise time, ischemia reduction, and symptom relief in 32 patients with refractory angina. Stem cell-based strategies, particularly involving endothelial progenitor cells (EPCs), have been applied for myocardial repair following infarction; EPCs home to ischemic sites, secrete paracrine factors to promote neovascularization, and contribute to vascular regeneration, as evidenced in preclinical models where EPC transplantation increased capillary density and improved cardiac function.^[93]^[94]^[95] Despite these advances, pro-neovascularization therapies face significant challenges, including transient effects from limited gene expression duration—plasmid-based vectors often yield short-lived transgene activity, reducing long-term efficacy—and off-target growth risks, such as unintended angiogenesis that could exacerbate tumors or cause edema. Regulatory hurdles persist, with no VEGF-based gene therapies approved by the FDA for pro-angiogenic indications as of 2025, due to inconsistent clinical outcomes and safety concerns in large-scale trials.^[96]^[97]^[98] Recent developments in the 2020s have focused on nanoparticle delivery systems to enable sustained release of pro-angiogenic factors, addressing transience issues in preclinical studies. For example, nanoporous silica nanoparticles loaded with VEGF have demonstrated controlled release over weeks in ischemic mouse models, enhancing stable neovascularization and tissue perfusion without bolus-related side effects. Similarly, hydrogel-embedded VEGF nanoparticles have shown improved angiogenic outcomes in hindlimb ischemia models, promoting mature vessel formation with reduced leakage. These innovations hold potential for more targeted and durable therapies in ischemic cardiovascular conditions.^[99]^[100]

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### Summary of VEGF Gene Therapy Trials for Intermittent Claudication or PAD (2020-2025)
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This VEGF-nano in a HA-TA hydrogel delivery system is successfully integrated with an appropriate device for clinical use, demonstrates promising angiogenic ...