Angiogenesis, the physiological process through which new blood vessels form from pre-existing vessels, plays a crucial role in health and disease. This process is fundamental to the growth and development of organisms, as well as the healing of wounds. However, it also contributes to the progression of various pathological conditions, including cancer, where it facilitates tumor growth and metastasis by supplying nutrients and oxygen. The mechanisms underlying angiogenesis are complex and highly regulated, balancing pro- and anti-angiogenic factors. These mechanisms can be divided into several key steps: activation of endothelial cells (ECs), basement membrane degradation, EC proliferation and migration, tube formation, and, ultimately, the maturation and stabilization of newly formed blood vessels (Shah and Lee 2024).
Activation of endothelial cells is typically initiated by signaling molecules such as VEGF, which binds to receptors on the surface of ECs. This binding initiates a cascade of intracellular signaling that leads to the expression of enzymes capable of degrading the basement membrane, thereby enabling the migration of endothelial cells. The migration and proliferation of endothelial cells are directed toward the source of angiogenic signals. These cells then align to form tubular structures, a process mediated by cell–cell adhesion molecules and extracellular matrix components. Finally, the new vessels mature and stabilize through pericyte recruitment and the deposition of a new basement membrane, ensuring the structural and functional integrity of the developing vasculature. The regulation of angiogenesis is a delicate equilibrium, with an array of growth factors, inhibitors, and environmental conditions influencing the process. Disruptions in this balance can lead to either excessive or insufficient angiogenesis, contributing to the pathogenesis of diseases. Therefore, understanding the mechanisms of angiogenesis is critical for developing therapeutic strategies to modulate angiogenesis in disease treatment and tissue engineering.
VEGF receptors belong to the family of tyrosine kinases that are transmembrane receptors implicated in angiogenesis and lymphangiogenesis. The activity of these receptors is regulated by key signaling molecules known as VEGF mitogens, such as VEGF A-D, which play a crucial role in vascular maintenance, development, and various pathological conditions (Ghalehbandi et al. 2023). There are three types of VEGF receptors, which include VEGFR-1, VEGFR-2, and VEGFR-3. VEGFR-1 has an affinity for VEGF-A and is involved in monocyte migration and hematopoiesis (Kaufman et al. 2021). This receptor also acts as a decoy receptor to control the availability of VEGF ligands and is expressed on the surface of monocytes, macrophages, and endothelial cells (Weddell et al. 2018). VEGFR-2 demonstrates robust tyrosine kinase activity, serving as a critical regulator of VEGF-induced angiogenesis. It is predominantly localized on the surface of endothelial cells, where it facilitates key signaling processes essential for vascular development (Shaik et al. 2020). It has a strong affinity for VEGF-A and promotes endothelial cell migration, proliferation, differentiation, and survival. On the other hand, VEGFR-3 is mainly expressed in lymphatic endothelial cells and has a strong affinity for VEGF-C and VEGF-D. It is important for lymphangiogenesis during embryonic development and is also involved in the regulation of vascular integrity and some pathological conditions, such as tumor-associated lymphangiogenesis (Korhonen et al. 2022).
However, this review article aims to summarize the molecular structure and function of VEGFR, with a particular focus on VEGFR-2, its molecular activation, and the signaling pathways it mediates. Additionally, it discusses the role of VEGFR-2 in the pathophysiology of angiogenesis-related diseases, therapies approved for treating VEGFR-2-regulated pathological angiogenesis, and associated resistance mechanisms.
