Endothelial protein C receptor-mediated endogenous and therapeutic transport of activated protein C across the blood-retina barrier protects the retina.

BACKGROUND

Activated protein C (APC) is a serine protease known for its anticoagulant, anti-inflammatory, and cytoprotective properties. Although clinical evidence links protein C (PC) deficiency to various retinal pathologies, the physiological role of APC in the retina remains unexplored.

OBJECTIVES

To determine whether PC and APC are synthesized locally in the healthy retina or are transported systemically across the blood-retina barrier (BRB) and to evaluate the contribution of the endothelial protein C receptor (EPCR) to APC transport and the therapeutic potential of APC in the retina following systemic administration.

METHODS

We utilized a unique and viable severe protein C deficiency murine model developed in our laboratory. Reverse transcription polymerase chain reaction, immunostaining, and coagulation-based activity assays were used to determine the presence and distribution of PC, APC, and EPCR in the retina and after APC injection via the tail vein. EPCR blockage was performed using an EPCR-neutralizing antibody. The anti-inflammatory activity of the APC analog, 3K3A-APC, was assessed in a murine model of retinal pathologies.

RESULTS

APC is not synthesized locally in the retina but originates from the systemic circulation, crosses the BRB, and accumulates in the retina. EPCR mediates the translocation of APC across the BRB. Systemically administered 3K3A-APC crosses the BRB and induces cytoprotective and anti-inflammatory effects in the retina comparable with intraocular treatment.

CONCLUSIONS

Our findings establish a fundamental step in investigating the concept of PC as a physiologically relevant, naturally protective protein in the eye. Our results support the feasibility of developing noninvasive, systemic APC-based therapies for retinal diseases.