Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling, and regeneration

Abstract

We report here the identification of an angiopoietin-related growth factor (AGF). To examine the biological function of AGF in vivo, we created transgenic mice expressing AGF in epidermal keratinocytes (K14-AGF). K14-AGF mice exhibited swollen and reddish ears, nose and eyelids. Histological analyses of K14-AGF mice revealed significantly thickened epidermis and a marked increase in proliferating epidermal cells as well as vascular cells in the skin compared with nontransgenic controls. In addition, we found rapid wound closure in the healing process and an unusual closure of holes punched in the ears of K14-AGF mice. Furthermore, we observed that AGF is expressed in platelets and mast cells, and detected at wounded skin, whereas there was no expression of AGF detected in normal skin tissues, suggesting that AGF derived from these infiltrated cells affects epidermal proliferation and thereby plays a role in the wound healing process. These findings demonstrate that biological functions of AGF in epidermal keratinocytes could lead to novel therapeutic strategies for wound care and epidermal regenerative medicine. S kin tissues, especially epidermis, are a barrier against the environment, which becomes accessible in wounds and various infections. An important goal in wound management is to achieve rapid wound closure. Analysis of gene activation in skin tissues shows that transforming growth factor-␣ (TGF-␣) (1) produced by keratinocytes and keratinocyte growth factor (KGF) (2, 3) made by dermal fibroblasts are both powerful growth factors for epidermal keratinocytes, indicating an important role for the interaction between dermis-epidermis in skin development. Although these two growth factors play critical roles in wound healing, gene inactivation studies show that these factors are not essential for epidermal growth or regeneration and suggest that regulation of epidermal growth is more complex than has been previously appreciated (4, 5).Angiopoietin-1 (Ang-1) (6) is a ligand for the receptor tyrosine kinase TIE2 (7,8), which contributes to signaling in angiogenesis (9). Ang-1 is characterized structurally by two domains, a coiled-coil domain and a fibrinogen-like domain (10). Recently, members of the angiopoietins (Angs) family have been identified by a domain homology-based molecular cloning strategy. One of these proteins, angiopoietin-related protein 2 (ARP2), was also reported as an angiogenic factor (11). Several recent reports demonstrate that angiopoietin-related proteins (ARPs) show pleiotropic effects not only on vascular cells but on cells of other lineages. For example, it has been shown that ANGPTL3 (12, 13) and FIAF͞PGAR͞ARP4 (14) may play central roles in lipid͞adipocyte metabolism as well as in angiogenesis. Here we identify, by screening EST databases, a previously undescribed angiopoietin-related growth factor (AGF), which is abundantly expressed in hepatocytes. To determine whether AGF promotes in vivo angiogenesis as does Ang-1, we created transgenic (TG) mice overexpressing mouse AGF in epi...

Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development

“…Recently, we (8)(9)(10) and others (11)(12)(13)(14)(15) identified several genes encoding proteins containing both the coiled-coil domain and the fibrinogen-like domain. Although these factors were initially predicted to function as ligands for Tie receptors, they bound neither Tie1 nor Tie2.…”

“…Therefore, they are currently orphan ligands and designated angiopoietin-like proteins (Angptls) or angiopoietin-related proteins (ARPs). Several studies show that Angptl͞ARP family proteins possess potent activities in the vascular system (8)(9)(10)(11)(12)(13)(14)(15)(16). Angptl1 and Angptl2 have been reported to possess weak endothelial cell-sprouting activities (11,12); however, there is little information as to their physiological functions.…”

Angiopoietin-related growth factor level in preeclampsia

“…Furthermore, statistically significant positive correlation was found between AGF and systolic blood pressure or mean arterial pressure in patients with preeclampsia. The overall effect of AGF is associated with angiogenesis and act as pro-angiogenic factors [10]; in addition, AGF can promote epidermal proliferation, remodeling and regeneration [11]. AGF can also affect glucose, lipid and energy metabolism.…”

Association between angiopoietin-like 6 (ANGPTL6) gene polymorphisms and metabolic syndrome-related phenotypes in the French MONICA Study

“…Its most interesting member (in terms of glucose, lipid homeostasis and insulin sensitivity) is ANGPTL6 (also called 'angiopoietin-related growth factor' [AGF]). ANGPTL6 was first identified in 2003, and has been characterized as an angiogenic factor involved in epidermal proliferation and wound healing [9,13]. Recently, it was shown that ANGPTL6 is involved in the development of obesity and its related insulin resistance in mouse models [14].…”

“…The mechanisms by which it stimulates energy expenditure and insulin sensitivity, and the nature of the tissues targeted by the protein have yet to be established. In mice, Angptl6 is expressed predominantly in the liver, but also in haematopoietic cells [13]. In humans, the ANGPTL6 gene is located on chromosome 19p13.2, but nothing is known of its expression and function.…”