Dual faces of angiogenesis: Mechanisms and therapeutic applications

Angiogenesis is a highly coordinated process essential for development, tissue homeostasis, and repair. In physiologic settings, endothelial cells remain quiescent until transient hypoxia- or injury-induced surges of VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), and other pro-angiogenic cues activate receptor tyrosine kinases, triggering MAPK (mitogen-activated protein kinase) and PI3K-AKT (phosphoinositide 3-kinase-AKT) cascades that drive sprouting, proliferation, migration, and vessel stabilization via pericyte recruitment and balanced Ang (angiopoietin)-Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2) signaling. In non-malignant pathologies, targeted pro-angiogenic therapies harness these mechanisms to restore perfusion in ischemic heart disease, chronic wounds, and neurovascular degeneration. In contrast, tumor-driven "malignant" angiogenesis subverts the same core pathways in both hypoxia-dependent and -independent manners. Oncogenic RAS (rat sarcoma)-RAF (rapidly accelerated fibrosarcoma)-MEK (MAPK/ERK kinase) and PI3K-AKT activity locks VEGFR2 (vascular endothelial growth factor receptor 2) Tyr1175 in a phosphorylated state, fueling unchecked endothelial proliferation and survival. Overexpression of integrin αvβ₃ (alpha-v beta-3) and NRP2 (neuropilin 2) amplifies FAK (focal adhesion kinase)-Src-mediated invasion, while glycocalyx shedding and uneven pericyte coverage produce leaky vasculature. Transient vessel normalization upon VEGF blockade is followed by adaptive resistance via HIF (hypoxia-inducible factor)-driven upregulation of FGF2, Ang-2 (angiopoietin-2), and HGF (hepatocyte growth factor)/c-Met pathways, necessitating complex combination regimens. Rationally distinguishing when to inhibit versus augment angiogenesis is therefore clinically decisive, because cancers demand vascular suppression/normalization whereas ischemic and degenerative disorders benefit from controlled pro-angiogenic repair. We compared malignant and non-malignant angiogenesis at the molecular and clinical levels, critically appraising therapies, from VEGF antibodies and multitarget TKIs (tyrosine kinase inhibitors) to pro-angiogenic growth factors and drug-delivery platforms, and their respective biomarkers (Ang-2, soluble VEGFR2, VEGF isoform ratios). By explicitly linking pathway mechanics to therapeutic choice, dosing, and biomarker-guided selection, this review provides a comprehensive roadmap for tailoring angiogenesis-targeted interventions, either to restrain pathological neovascularization in cancer or to promote reparative vessel growth in ischemic and degenerative disease.