**Background:** Angiogenesis—the formation of new blood vessels from pre-existing vasculature—is a fundamental process in development, physiology, and disease. This narrative review by Dudley and Griffioen provides a comprehensive overview of the mechanisms of pathological angiogenesis and its therapeutic implications across multiple disease states. The authors emphasize that endothelial cells (ECs) are highly heterogeneous, both spatially and transcriptionally, and that this heterogeneity makes targeted therapeutic approaches both possible and challenging. The review covers founding concepts including the angiogenic switch (tissue growth beyond approximately 1 mm³ requires new vasculature) and the central role of hypoxia-inducible factors (HIFs), for which Semenza, Kaelin, and Ratcliffe received the 2019 Nobel Prize.
**Methods:** The authors synthesized the primary and review literature across vascular biology, oncology, immunology, and multiple clinical specialties. They describe multiple modes of vascularization: (1) sprouting angiogenesis driven by VEGF gradient-dependent tip cell migration and Notch/Dll4-mediated tip/stalk cell selection; (2) intussusceptive (splitting) angiogenesis, a rapid process occurring within hours to minutes; (3) coalescent angiogenesis, where smaller vessels fuse into larger ones; (4) vessel co-option, where tumors grow along pre-existing vessels without inducing new sprouting; and (5) vasculogenic mimicry (VM), where cancer cells trans-differentiate and masquerade as ECs, expressing markers such as VE-cadherin, Tie-1, and PECAM. Endothelial progenitor cells, including circulating endothelial colony-forming cells (ECFCs) which constitute approximately 0.05–0.2 cells/mL of blood, and vessel wall-resident endovascular progenitors (EVPs) expressing markers such as Sox18, IL33, EGFR, and PDGFRα, are also discussed.
**Key Results:** The review details pathological angiogenesis across multiple diseases. In cancer, anti-angiogenic therapy produces robust pre-clinical effects but has been less effective in human patients due to resistance mechanisms, including compensatory upregulation of alternative growth factors and switches to non-angiogenic growth modes. However, seven combination studies of immune checkpoint inhibitors plus angiogenesis inhibitors have yielded eight FDA approvals since 2018. In renal cell carcinoma, axitinib combined with avelumab or pembrolizumab doubled overall response rates. In hepatocellular carcinoma, atezolizumab plus bevacizumab produced 18% complete remissions compared to 0% without bevacizumab. In endometrial carcinoma, pembrolizumab plus lenvatinib significantly improved outcomes. The review identifies endothelial cell anergy—where angiogenic tumor ECs become unresponsive to inflammatory cytokines and fail to upregulate adhesion molecules such as ICAM-1, VCAM-1, and E-selectin—as a vascular immune checkpoint that can be overcome by angiogenesis inhibitors. In atherosclerosis, neovascularization correlates with unstable plaques and plaque rupture, and angiogenesis inhibitors have been shown to reduce plaque growth and promote stable phenotypes in apolipoprotein E-deficient mice. In arthritis, angiogenesis is an early feature driven by inflammatory cytokines and hypoxia; inhibition of HIF-1α and VEGF signaling has shown suppressive effects in collagen-induced rat models. In endometriosis, which affects approximately 10% of women of reproductive age, overexpression of VEGFA and increased microvessel density have been observed. In obesity, white adipose tissue is one of the most vascularized tissues with every adipocyte surrounded by one or more capillaries; treatment with anti-angiogenic agents such as TNP-470, thalidomide, and endostatin mimics reduced adipose tissue in pre-clinical models. The review also covers ocular diseases (diabetic retinopathy, age-related macular degeneration), psoriasis (affecting 2–4% of individuals), vascular malformations including cerebral cavernous malformations (CCMs) and lymphatic malformations with hotspot PIK3CA and NRAS mutations, and the emerging understanding of COVID-19 as a vascular disease characterized by microvascular injury, endothelialitis, and circulating markers of EC dysfunction.
**Clinical Implications:** The authors conclude that targeting pathological angiogenesis extends well beyond oncology to numerous benign diseases, though long-term use of angiogenesis inhibitors must account for effects on physiological angiogenesis such as wound healing. The success of combining anti-angiogenic therapy with immunotherapy—currently supported by eight FDA approvals—validates the hypothesis that overcoming angiogenesis-induced EC anergy potentiates anti-tumor immunity. Emerging approaches including vessel normalization (which paradoxically improves chemotherapeutic delivery), angiocrine signaling, endothelial plasticity and endothelial-to-mesenchymal transition (EndMT), and high endothelial venule (HEV) neogenesis in tumors offer new therapeutic avenues. The authors highlight that resistance to anti-angiogenic drugs in cancer remains a significant challenge, driven by growth factor redundancy, tumor cell plasticity, bone marrow-derived immune cells, cancer-associated fibroblasts, and transitions to non-angiogenic growth modes such as vessel co-option and vasculogenic mimicry. Future directions include artificial intelligence and machine learning for rational drug combination design, biomarker identification, and diagnosis in multiple pathological settings.