Background: The maintenance of a quiescent retinal vascular endothelial barrier is paramount for tissue supply and homeostasis to ensure visual function. Chronic hyperglycemia in diabetes causes structural and functional alterations of the endothelium that are accelerated by the production of several mediators such as VEGF. The disturbance of interendothelial junction stability leading to retinal hyperpermeability is one of the changes leading to diabetic macular edema (DME) that can occur at any stage of diabetic retinopathy. Advances in our understanding of the pathophysiological mechanisms of DME have enabled effective new therapies such as anti-VEGF’s, which are however associated with non-negligible side effects. The discovery of endothelium-specific protective targets that could restore retinal endothelial quiescence could provide a therapeutic alternative. Signaling mediated by BMP9 circulating protein via its endothelium-specific receptor ALK1, is known for its role in the maintenance of vascular quiescence. However, its ability to protect the endothelium and prevent vascular permeability has not been tested in the context of diabetes.