Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy

Abstract

SignificanceIn proliferative diabetic retinopathy (PDR), the most vision-threatening sequela of diabetic eye disease, retinal ischemia leads to increased expression of angiogenic factors that promote neovascularization. Although therapies targeting the potent angiogenic mediator vascular endothelial growth factor have been remarkably successful for the treatment of diabetic macular edema, this approach has not proven sufficient to prevent the development of retinal neovascularization, implicating additional angiogenic factor(s) in PDR pathogenesis. We demonstrate here that angiopoietin-like 4 is a potent angiogenic mediator with markedly increased expression in the eyes of PDR patients. Our studies identify a novel therapeutic target for the treatment of ocular neovascular disease and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis.

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…Blockade of this interaction could postpone the recovery from peak proteinuria in mice models of kidney diseases 41, 42. Furthermore, on the one hand, ANGPTL4 promotes endothelial cell integrity and improves angiogenesis for cerebral protection in ischemic stroke; on the other hand, upregulation of ANGPTL4 in hypoxic Müller cells accelerates abnormal angiogenesis and retinopathy 43. Collectively, ANGPTL4 is a double‐edged sword in different diseases.…”

Expression Pattern of HIF-1α and VEGF Supports Circumferential Application of Scatter Laser for Proliferative Sickle Retinopathy

“…16–19 Immunohistochemical detection of glial fibrillary acidic protein (GFAP; Sigma-Aldrich Corp., St. Louis, MO, USA) and CD34 (Covance) was performed in paraffin-embedded tissue sections by using an ABC system as previously described. 20 …”

“…16–18 Images were captured with the confocal microscope 710 LSM (Carl Zeiss, Inc., Oberkochen, Germany).…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…And the secreted factors observed in neovascularization, including VEGF, TNF-α, and IL-1β, are elevated also in macular edema (Cuff et al 1996;Luna et al 1997). Similarly, ANGPTL4, an emerging target in pathological angiogenesis and retinal neovascularization (Babapoor-Farrokhran et al 2015) may also play an important role in vascular permeability and macular edema . The downstream signaling molecules are also similar between retinal neovascularization and diabetic macular edema.…”

“…MMPs are necessary to degrade the basement membrane to allow migrating vascular endothelial cells to escape from the parent vessel . Although therapies targeting MMPs have not proven successful, other molecules that regulate extracellular matrix protein production have emerged as potential targets including transforming growth factor (TGF)-α and -β, endoglin, epidermal growth factor (EGF), inflammatory cytokines Babapoor-Farrokhran et al (2015), Xin et al (2013), and Kwon et al (2015) Stromal-derived factor-1 (SDF-1) and its receptor CXCR4 Ghanem et al (2014) Metabolic gene products Treps et al (2016) Matrix metalloproteinases (MMP) Sampieri et al (2013), Chang et al (2016) Inflammation and inflammatory cytokines de Oliveira Dias et al (2011) and Schor and Schor (2010) Reactive oxygen species (ROS) Wilkinson-Berka et al (2013) Stem cell and endothelial progenitor therapy Nazari et al (2015) Integrin antagonists Salehi-Had et al (2011), Varner et al (1996, and Tolentino (2009) Methionine aminopeptidase Ma et al (2011) andMauriz et al (2010) including IL-6 and 8, TNF-α and β inhibitors, α5β1 integrin receptor inhibitor, and α v β 3 and α v β 5 . Another critical step in pathological angiogenesis is the promotion of endothelial cell survival through both intrinsic (e.g., VEGF) and extrinsic mechanisms.…”