BMP9 (Bone Morphogenetic Protein-9)/Alk1 (Activin-Like Kinase Receptor Type I) Signaling Prevents Hyperglycemia-Induced Vascular Permeability

Arterioscler Thromb Vasc Biol. 2018 Aug;38(8):1821-1836. doi: 10.1161/ATVBAHA.118.310733.


Objective- Diabetic macular edema is a major cause of visual impairment. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. However, long-term intravitreal use of anti-VEGFs is associated with potential safety issues, and the identification of alternative regulators of vascular permeability may provide safer therapeutic options. The vascular specific BMP (bone morphogenetic protein) receptor ALK1 (activin-like kinase receptor type I) and its circulating ligand BMP9 have been shown to be potent vascular quiescence factors, but their role in the context of microvascular permeability associated with hyperglycemia has not been evaluated. Approach and Results- We investigated Alk1 signaling in hyperglycemic endothelial cells and assessed whether BMP9/Alk1 signaling could modulate vascular permeability. We show that high glucose concentrations impair Alk1 signaling, both in cultured endothelial cells and in a streptozotocin model of mouse diabetes mellitus. We observed that Alk1 signaling participates in the maintenance of vascular barrier function, as Alk1 haploinsufficiency worsens the vascular leakage observed in diabetic mice. Conversely, sustained delivery of BMP9 by adenoviral vectors significantly decreased the loss of retinal barrier function in diabetic mice. Mechanistically, we demonstrate that Alk1 signaling prevents VEGF-induced phosphorylation of VE-cadherin and induces the expression of occludin, thus strengthening vascular barrier functions. Conclusions- From these data, we suggest that by preventing retinal vascular permeability, BMP9 could serve as a novel therapeutic agent for diabetic macular edema.

Keywords: activin receptors; capillary permeability; mice; occludin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / deficiency
  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Capillary Permeability / drug effects*
  • Cell Line
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / therapy*
  • Diabetic Retinopathy / chemically induced
  • Diabetic Retinopathy / genetics
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / prevention & control*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Genetic Therapy / methods*
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors* / biosynthesis
  • Growth Differentiation Factors* / genetics
  • Growth Differentiation Factors* / pharmacology
  • Haploinsufficiency
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hyperglycemia / chemically induced
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / therapy*
  • Macular Edema / chemically induced
  • Macular Edema / genetics
  • Macular Edema / metabolism
  • Macular Edema / prevention & control*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Streptozocin
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Blood Glucose
  • GDF2 protein, human
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • Smad Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Streptozocin
  • KDR protein, human
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse