IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Abstract

We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit ؉ ), stem cell antigen-1 (sca-1 ؉ ), hematopoietic stem cell (HSC), or CD34 ؉ endothelial precursor cell (EPC) function. Exposure of CD34 ؉ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygeninduced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions. IGFBP3 ͉ angiogenesis ͉ retinopathy of prematurity V ascular damage associated with diabetic retinopathy and retinopathy of prematurity (ROP) results from tissue ischemia, and, subsequently, this ischemia leads to development of pathological neovascularization. Insulin-like growth factor 1 (IGF1) is required for normal retinal vascular development because vascular development is arrested in its absence despite the presence of VEGF (1). Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4-13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).The effects of IGF1 are mediated by IGF1R and modulated by complex interactions with IGF binding proteins (IGFBPs), which are also modulated at multiple levels. Six IGFBPs function as transporter proteins and storage pools for IGF1 in a tissue-and developmental stage-specific manner. Phosphorylation, proteolysis, polymerization (8), and cell or matrix association (9) regulates the functions of IGFBPs. Specific IGFBPs have been shown to either stimulate or inhibit IGF1 action (10).IGFBP3, the best studied and most abundant of these binding proteins, carries Ն75% of serum IGF1 and IGF2 in heterotrimeric complexes. Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-in...

Serum concentrations of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and cardiovascular risk factors in adolescents

“…Given the growth-promoting effect of the IGF system, increased cardiovascular risk may be related to the dysregulation of angiogenesis and endothelial dysfunction by the IGF system. 29,30 It has been shown that IGFBP-3 modulates stem cell receptor, regulates the cellular function of haematopoietic stem cells and mediates endothelial precursor cell migration, differentiation and capillary formation in vitro. 29 Overexpression of IGFBP-3 and subsequent high circulating IGFBP-3 concentration may represent a physiological adaptation to ischaemia.…”

“…29,30 It has been shown that IGFBP-3 modulates stem cell receptor, regulates the cellular function of haematopoietic stem cells and mediates endothelial precursor cell migration, differentiation and capillary formation in vitro. 29 Overexpression of IGFBP-3 and subsequent high circulating IGFBP-3 concentration may represent a physiological adaptation to ischaemia. It has been shown that IGFBP-3 activates sphingosine kinase in human endothelial cells and may positively regulate angiogenesis through this pathway.…”

Endothelial cells and the IGF system

“…IGFBP3 expression was regulated by hypoxia and it promoted differentiation of EPCs to endothelial cells. IGFBP3 also increased EPC migration, VEGFR1 and VEGFR 2 expression, and tube formation in vitro (Chang et al 2007), as well as NO synthesis, which is required for homing into ischaemic tissue (Kielczewski et al 2009). Igfbp3-deficient mice have more vessel loss after high oxygen exposure and less vessel regrowth after restoration of normoxia in a model of oxygen-induced retinopathy (Lofqvist et al 2007).…”

“…IGFBP3 has also been studied in oxygen-induced retinopathy (Chang et al 2007, Lofqvist et al 2007). IGFBP3 expression was regulated by hypoxia and it promoted differentiation of EPCs to endothelial cells.…”

“…The authors postulated that IGFBP3 might prevent retinal neovascularisation by inhibiting oxygen-induced vascular loss and promoting regrowth after vascular destruction. In support of this, plasmid-mediated IGFBP3 overexpression protected the retina from hyperoxia-induced vascular regression and subsequent neovascularisation (Chang et al 2007). …”