Ursodeoxycholic Acid Attenuates the Retinal Vascular Abnormalities in Anti-PDGFR-β Antibody-Induced Pericyte Depletion Mouse Models

Abstract

As a clinical manifestations of diabetic retinopathy (DR), pericytes (pcs) loss from the capillary walls is thought to be an initial pathological change responsible for the breakdown of the blood-retinal barrier (BRB). This study was performed to investigate the effects of ursodeoxycholic acid (UDCA) in pc depletion mice by injection of an antibody against platelet-derived growth factor reception-β (pDGfR-β clone APB5). To assess the integrity of the retinal vessels, their density, diameters, vessel branching points, and number of acellular capillaries were evaluated. While all types of retinal vessels became enlarged in APB5-induced mice, treatment with UDCA rescued the vasculature; the vessel density, diameter of the veins and capillaries, and vessel branching points were significantly lower in mice treated with UDCA. Although APB5-induced mice displayed progressive exacerbation of retinal edema, whole retinal thickness upon treatment with UDCA was significantly decreased. Additionally, UDCA reduced the expression of F4/80 + macrophages in the APB5-induced retina according to immunofluorescent labeling. UDCA also reduced the increased expression of angiogenic factors and inflammatory mediators (vascular endothelial growth factor, intercellular adhesion molecule-1, and monocyte chemotactic protein-1). These findings suggest that UDCA can be used to prevent the progression of and treat DR. Diabetes and its related complications, including retinopathy, have a great social and economic burden worldwide 1,2. The World Health Organization has suggested that diabetic retinopathy (DR) is responsible for 15-17% of total blindness cases in the United States and Europe 1,3-5. Pericytes (PC) not only provide mechanical support, but also maintain vessel wall integrity by interacting with endothelial cells (EC) via secretory signals and direct cell-to-cell contact 6. As an early clinical manifestation of DR, PC depletion from the capillary wall is considered an early pathological change that causes the blood-retinal barrier (BRB) to collapse and subsequent vascular hyperpermeability 7. Furthermore, PC depletion results in vascular abnormalities along with upregulation of angiogenic factors and inflammatory cytokines 8,9. In cases of more advanced DR, vascular occlusion induces retinal hypo-perfusion and hypoxia, resulting in abnormal angiogenesis that directly causes blindness due to vitreous hemorrhage and tractional retinal detachment 10. In recent years, intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents have been effectively used to treat diabetic macular edema 11-13 and have also empirically indicated the involvement of the VEGF signaling and inflammation in BRB breakdown in DR 14. However, frequent injections are burdensome for patients and physicians, and are associated with a very high cost to the healthcare system. Preventative medicine of DR with a safe and low-burden treatment for patients that requires investigation. Ursodeoxycholic acid (UDCA), a product of the hydrolysis of taurour...

Glycine-Conjugated Bile Acids Protect RPE Tight Junctions against Oxidative Stress and Inhibit Choroidal Endothelial Cell Angiogenesis In Vitro

“…The bile acids ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been shown to protect against photoreceptor cell loss in multiple models of inherited retinal degeneration [ 2 , 3 , 4 , 5 , 6 ]. More recently, studies have investigated potential protective roles for UDCA [ 7 ] and TUDCA [ 8 , 9 ] against the development and progression of diabetic retinopathy in rodent models. However, few studies have examined bile acids in RPE cells or in CECs, the two cell types most prominently involved in AMD pathophysiology.…”

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

“…TUDCA was able to prevent cell death induced by elevated glucose through its anti-apoptotic and antioxidant properties in cultured retinal neural cells. Together, these results suggest that UDCA and TUDCA attenuate retinal vascular and neural abnormalities associated with DR [ 93 , 94 ].…”

“…UDCA clearly attenuates the increase in ER stress and prevents loss of pericytes and vascular integrity in DR [ 93 ]. Another recent study investigated the effects of UDCA in pericyte depletion mice by injection of an antibody against platelet-derived growth factor reception-β (PDGFR-β clone APB5) [ 94 ]. UDCA reduced the expression of F4/80+ macrophages in the APB5-induced retina according to immunofluorescent labeling.…”

Role of pericytes in the development of cerebral cavernous malformations

“… 8 , 9 Knockout or blockage of PDGFRβ caused a loss of pericytes and dysfunction in the tight junction of ECs, 10 , 11 enlarged the capillaries, and decreased the vessel branching points. 12 The decrease in pericytes also promotes the development of arteriovenous malformation. 13 However, whether inhibition of pericyte function aggravates CCM lesions is yet to be elucidated.…”