ANGPT4

ANGPT4 Full Name

angiopoietin 4

ANGPT4 Introduction

ANGPT4 (also known as angiopoietin-4) is a member of the angiopoietin family of growth factors, which play critical roles in angiogenesis, vascular remodeling, and metabolic regulation. Unlike the well-characterized ANGPT1 and ANGPT2, which bind the Tie2 receptor tyrosine kinase, ANGPT4 exhibits unique tissue distribution and functional properties. The gene encodes a secreted glycoprotein that is proteolytically processed to generate an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain, the latter being responsible for receptor binding. ANGPT4 is highly expressed in the heart, placenta, and certain cancer types, where it modulates endothelial cell survival, vascular permeability, and metabolic homeostasis. Its role is context-dependent, acting as an agonist or partial antagonist of Tie2 depending on the cellular environment, and it has been implicated in lymphatic development, inflammatory responses, and tumor angiogenesis.

Figure 1. Schematic structure of angiopoietin 4.

Gene Structure and Protein Architecture
The human ANGPT4 gene is located on chromosome 20p13 and spans approximately 9.5 kb, containing 8 exons. Alternative splicing produces two major transcript variants. The full-length protein consists of 503 amino acids with a calculated molecular weight of approximately 57 kDa. Like all angiopoietins, ANGPT4 contains:
A signal peptide (amino acids 1-17) for secretion.
An N-terminal coiled-coil domain (approximately amino acids 18-250) that mediates homo-oligomerization, forming dimers and higher-order multimers essential for receptor activation.
A C-terminal fibrinogen homology domain (approximately amino acids 260-503) that directly binds to the Tie2 receptor (and possibly integrins). This domain adopts a globular structure stabilized by disulfide bonds.
Proteolytic cleavage by unknown proteases may generate separate N-terminal and C-terminal fragments with distinct biological activities, as observed for other angiopoietins.

Biological Functions in Normal Physiology and Disease
In the heart, ANGPT4 contributes to vascular integrity and cardiac function by promoting endothelial cell survival under stress conditions such as ischemia and oxidative stress, while also reducing vascular leakage through strengthening endothelial cell-cell junctions. Cardiac-specific overexpression of ANGPT4 in mice improves recovery after myocardial infarction, reducing infarct size and preserving left ventricular function. In the placenta, ANGPT4 regulates trophoblast invasion, spiral artery remodeling, and fetoplacental blood flow, and reduced placental expression has been associated with preeclampsia and intrauterine growth restriction. ANGPT4 also plays a non-redundant role in lymphatic vessel formation, promoting the proliferation and migration of lymphatic endothelial cells and being required for proper lymphatic valve formation. In cancer, ANGPT4 is overexpressed in colorectal cancer, gastric cancer, breast cancer, and glioblastoma, where it promotes tumor angiogenesis and directly enhances cancer cell proliferation, migration, and invasion. High ANGPT4 expression correlates with advanced tumor stage, metastasis, and poor patient survival in several malignancies. Additionally, ANGPT4 is upregulated in inflammatory bowel disease and rheumatoid arthritis, where it promotes monocyte and macrophage recruitment, exacerbating chronic inflammation.

Alternate Names for ANGPT4

ANGPT4; angiopoietin 4; AGP4; ANG4; ANG-3; angiopoietin-4; ANG-4; angiopoietin-3; dJ824F16.2 (angiopoietin 4);