The cardiovascular system, also known as the circulatory system, is the organ system responsible for transporting oxygen, nutrients, hormones, and other essential substances throughout the body, while removing waste products. It plays a vital role in maintaining homeostasis and supporting the overall function of various organ systems. The main components of the cardiovascular system are the heart, blood vessels, and blood^[1][2].

The major cell types in the cardiovascular system include cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts, neuronal cells, immune cells, adipocytes, and vascular pericytes. Interactions among these cell types regulate key physiological processes, such as cardiac muscle contraction, extracellular matrix (ECM) remodeling, neuronal control within the cardiac tissue, vasoregulation, leukocyte trafficking, and permeability at the microcirculation level. These dynamic interactions span multiple biological scales, collectively shaping the local microenvironment^[3].

Angiogenesis is a critical process in organ and tissue formation, involving the development of new blood vessels from existing capillaries to establish a complete, organized, and mature vascular network. This process entails the degradation of the basement membrane, as well as the activation, proliferation, and migration of endothelial cells (ECs), all tightly regulated by a balance between pro-angiogenic and anti-angiogenic factors. Angiogenesis is essential not only for physiological conditions such as tissue growth and repair but also for pathological conditions such as tumor progression and survival^[2][3].

Angiogenic growth factors

Angiogenic growth factors are a class of molecules that play a fundamental role in blood vessel formation. Numerous angiogenic growth factors and their associated signaling pathways are involved in regulating the early stages of vascular development^{[3][5][6][7][8]}.

Vascular endothelial growth factor (VEGF) family

The VEGF family is the primary angiogenic molecule during organogenesis, as well as in postnatal physiological and pathological angiogenesis. It is the most potent stimulator of endothelial cell proliferation, sprouting, migration, and tube formation, and serves as a powerful survival factor and permeability regulator for endothelial cells. The VEGF family includes VEGF-A, VEGF-B, placental growth factor (PLGF), VEGF-C, and VEGF-D, along with their corresponding receptors VEGFR-1, VEGFR-2, and VEGFR-3^[5].

VEGFs

VEGFRs

Platelet-derived growth factor (PDGF) family

All PDGF family members exhibit strong angiogenic activity in animal studies. PDGFs promote vascular maturation by recruiting mural cells^[3][9].

PDGFs

PDGFRs

Fibroblast growth factor (FGF) family

FGFs have a wide range of biological functions, including roles in mitosis, cell migration, differentiation, pluripotency, wound healing and angiogenesis. Among the FGF family members, FGF1 and FGF2 exhibit the most prominent angiogenic activity^{[10][11][12][13]}.

FGFs

FGFRs

HGF/c-Met

The HGF/c-Met signaling pathway plays a crucial role in wound healing, tissue regeneration, and embryo development. Acting synergistically with the VEGF/VEGFR pathway, the HGF/c-Met signaling pathway regulates angiogenesis and promotes tumor invasion and metastasis^[14].

HGF

c-Met

Angiopoietins

Angiopoietins (ANGPTs) are growth factors that regulate the development, maintenance, and remodeling of blood vessels. They play a key role in controlling tumor growth and angiogenesis. The main members of this family include Ang1, Ang2, Ang3, and Ang4, with Ang1 and its receptor Tie2 being the most extensively studied. The Ang1/Tie2 signaling pathway functions primarily in the later stages of angiogenesis, where it promotes endothelial cell migration and supports their survival^[13][15][16].

EGF/EGFRs

EGF is involved in cell growth, proliferation, differentiation, migration, adhesion, apoptosis, and tumor angiogenesis, through EGFR. It promotes endothelial cell proliferation and differentiation by activating downstream signaling pathways (MAPK, PI3K/AKT/PKB, STAT, and PLCγ/PKC). Additionally, EGF stimulates mitosis and upregulates the synthesis, expression, and secretion of angiogenic factors such as VEGF, partly via Ang2, thereby indirectly promoting tumor angiogenesis.

EGF

EGFRs

IGFs/IGFBPs

In ECs, IGF-1 (Insulin-like growth factor-1) stimulates the expression of angiogenesis-related growth factors by activating the PI3-kinase/Akt pathway. IGF-2 and IGF-1R are critical for tip cell maintenance and sprouting angiogenesis. IGFBPs (Insulin-like growth factor binding proteins) are a family of proteins necessary for binding and transporting IGFs. IGFBPs play key roles in physiological and pathological angiogenesis^[17][18].

IGF-1

IGF-2

IGFBPs

TGF-β

TGF-β regulates angiogenesis through multiple mechanisms. For example, it regulates vascular proliferation and maturation by modulating ALK1 and ALK5 signaling cascades, which exert opposing effects. In addition, TGF-β can promote its own expression and upregulate other angiogenic factors, such as PDGF, IL-1, bFGF, TNF-α, and TGF-α^[20].

Other proteins that are not conventionally classified as growth factors also can promote angiogenesis, including erythropoietin (EPO) and stromal cell-derived factor-1 (SDF-1)^[21].

Cell adhesion molecules (CAM) in angiogenesis

During angiogenesis, the adhesive capacity of endothelial changes under the influence of pro-angiogenic factors and is regulated by the dynamic modulation of the CAMs. During tumor angiogenesis, CAMs such as integrins, cadherins, selectins, and immunoglobulins, participate in the process through mediating cell–cell and cell–matrix interaction and thereby regulating neo vessel extension and maturation^[22].

Integrins

Integrins are key adhesion molecules in the extracellular matrix, regulating communications between cells and their surroundings.

Through interacting with soluble ligands, ECM and cell surface-bound ligands (such as growth factors, proteases, cytokines), structural components of the ECM (such as collagen and fibronectin), plasma proteins, microbial pathogens, and immune cell receptors, integrins play a crucial role in cell homeostasis, immunity, inflammation, infection, thrombosis, lymphangiogenesis, angiogenesis, and tumorigenesis.

αvβ3 is essential for angiogenesis driven by bFGF and TNF-α signaling, whereas αvβ5 mediates angiogenesis via TGF-α and VEGF. Additionally, αvβ5 enhances VEGF-induced vascular permeability and promotes tumor metastasis^[3][22].

Netrins

Netrins are a family of ECM-associated proteins characterized by laminin-like domains. They are known to regulate several fundamental biological processes, including morphogenesis, tumorigenesis, and adhesion. More recently, they have also been recognized for their emerging role in angiogenesis^[23].

Cadherins

The cadherin family consists of calcium-dependent adhesion molecules that are essential for cell-cell recognition and adhesion in solid tissues. Vascular endothelial (VE)-cadherin, specific to ECs, localizes at cell junctions and regulates vascular development, permeability, and tumor angiogenesis, extendingbeyond its traditional adhesive function^[22][24][25].

Proteinases

Matrix metalloproteinases (MMPs): Certain MMPs promoting angiogenesis by detaching pericytes, releasing angiogenic growth factors, exposing cryptic proangiogenic integrin binding sites in the ECM, generating promigratory ECM component fragments, and disrupting endothelial cell-cell adhesions^[26](Learn more about MMPs).

A Disintegrin and Metalloproteinase (ADAMs): Activated ADAMs contribute significantly to cardiovascular processes by regulating vascular smooth muscle cell proliferation and migration, promoting angiogenesis, modulating vascular cell apoptosis and survival, as well as supporting tissue repair and wound healing^[27].

MMPs

ADAMs

Signaling proteins

Semaphorins

Semaphorins participate in the process of angiogenesis by regulating the balance between promoting and inhibiting angiogenesis. Similar to their role in axonal guidance, semaphorins direct endothelial cells toward tube formation. Representative pro-angiogenic semaphorins include Sema3C, Sema4A, Sema4D, Sema6D, and Sema7A, while representative anti-angiogenic semaphorins include Sema3A, Sema3B, Sema3D, Sema3E, and Sema3F. Notably, Sema3C and Sema4A also exhibit both pro- and anti-angiogenic activity^[28].

Notch

Notch signaling is a key regulator of vessel formation, controlling endothelial cell specialization, proliferation, migration, adhesion, and arterial-venous differentiation^[29].

Survivin

Survivin (BIRC5), a member of the inhibitor of apoptosis proteins (IAPs) family, plays roles in cell division, inhibition of apoptosis, and angiogenesis. It is highly expressed in most human cancers, promoting tumor survival by reducing apoptosis and enhancing endothelial cell proliferation and migration^[30][31].

Ephrins/EphR

Ephrins and their receptors (EphRs) participate in the remodeling of both blood and lymphatic vasculature by mediating cell-cell contact–dependent juxtacrine signaling, adhesion to the extracellular matrix, and cell migration. They play a vital role in the function of endothelial cells, pericytes, and vascular smooth muscle cells. Moreover, Ephrins/EphRs are also implicated in pathological angiogenesis, such as tumor neovascularization^[32].