Title:
Blood-retina barrier breakdown in pericyte-free vessels

 

Akiyoshi Uemura
Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences
1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

 

Abstract:
In the central nervous system, the endothelial cells (ECs) and the surrounding pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural and glial homeostasis. However, in diabetic retinopathy (DR), the dropout of PCs from capillary walls is assumed to cause breakdown of the blood–retina barrier (BRB) and subsequent vision–threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by transiently inhibiting the PC recruitment to developing retinal vessels using an anti-platelet-derived growth factor receptor beta antibody (1), we have established a new mouse model that reproduces various forms of DR, including hyperpermeability, hypoperfusion, and hypoxia. Notably, PC depletions directly evoked inflammatory responses in ECs and sustained the perivascular infiltration of macrophages expressing vascular endothelial growth factor (VEGF) receptor 1. The EC-macrophage interactions via VEGF, placental growth factor, and angiopoietin-2 led to an irreversible BRB breakdown. This cycle was efficiently shut down by simultaneous blockade of these signals, thus restoring the EC-PC association and the BRB integrity. Our experimental model will provide a new drug discovery system, not only for DR, but also for neurological disorders and diabetic microvascular complications.

 

References:
1．Uemura A. et al. Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest. 110:1619-1628 (2002)