LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation

Arterioscler Thromb Vasc Biol. 2016 Feb;36(2):350-60. doi: 10.1161/ATVBAHA.115.306713. Epub 2015 Dec 3.


Objective: We recently demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) is required for cardiovascular development in zebrafish. However, what role LRP1 plays in angiogenesis remains to be determined. To better understand the role of LRP1 in endothelial cell function, we investigated how LRP1 regulates mouse retinal angiogenesis.

Approach and results: Depletion of LRP1 in endothelial cells results in increased retinal neovascularization in a mouse model of oxygen-induced retinopathy. Specifically, retinas in mice lacking endothelial LRP1 have more branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Increased endothelial proliferation as detected by Ki67 staining was observed in LRP1-deleted retinal endothelium in response to hypoxia. Using an array of biochemical and cell biology approaches, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1) directly interacts with LRP1 in human retinal microvascular endothelial cells. This interaction between LRP1 and PARP-1 decreases under hypoxic condition. Moreover, LRP1 knockdown results in increased PARP-1 activity and subsequent phosphorylation of both retinoblastoma protein and cyclin-dependent kinase 2, which function to promote cell cycle progression and angiogenesis.

Conclusions: Together, these data reveal a pivotal role for LRP1 in endothelial cell proliferation and retinal neovascularization induced by hypoxia. In addition, we demonstrate for the first time the interaction between LRP1 and PARP-1 and the LRP1-dependent regulation of PARP-1-signaling pathways. These data bring forth the possibility of novel therapeutic approaches for pathological angiogenesis.

Keywords: angiogenesis; endothelial cells; hypoxia; low-density lipoprotein receptor–related protein 1; poly(ADP-ribose) polymerases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Hypoxia
  • Cell Proliferation*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Disease Models, Animal
  • Endothelial Cells / enzymology*
  • Endothelial Cells / metabolism
  • Genotype
  • HEK293 Cells
  • Humans
  • Hypoxia / complications
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Mice, Knockout
  • Phenotype
  • Phosphorylation
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • RNA Interference
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Retinal Neovascularization / enzymology*
  • Retinal Neovascularization / etiology
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / pathology
  • Retinal Vessels / enzymology*
  • Retinal Vessels / pathology
  • Retinoblastoma Protein / metabolism
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Receptors, LDL
  • Retinoblastoma Protein
  • Tumor Suppressor Proteins
  • PARP1 protein, human
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2