Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells.
Interactions between endothelial cells (ECs) and perivascular mural cells (MCs) via signaling molecules or physical contacts are implicated both in vascular remodeling and maintenance of vascular integrity. However, it remains unclear how MCs regulate the morphogenic activity of ECs to form an organized vascular architecture, comprising distinct artery, vein, and capillary, from a simple mesh-like network. A clear elucidation of this question requires an experimental model system in which ECs are separated from MCs and yet form vascular structures. Here we report that injection of an antagonistic mAb against PDGFR-beta into murine neonates provides such an experimental system in the retina by completely blocking MC recruitment to developing vessels. While a vascular network was formed even in the absence of MCs, it was poorly remodeled and leaky. Using this vascular system ideal for direct assessment of the activities of MC-derived molecules, we show that addition of recombinant modified angiopoietin-1 restored a hierarchical vasculature, and also rescued retinal edema and hemorrhage in the complete absence of MCs. These observations demonstrate the potential of Ang1 as a new therapeutic modality for MC dropout in diseases such as diabetic retinopathies.
Uemura
Akiyoshi
A
Department of Molecular Genetics, Kyoto University Graduate School of Medicine, Kyoto, Japan. auemura@kuhp.kyoto-u.ac.jp
Ogawa
Minetaro
M
Hirashima
Masanori
M
Fujiwara
Takashi
T
Koyama
Shinji
S
Takagi
Hitoshi
H
Honda
Yoshihito
Y
Wiegand
Stanley J
SJ
Yancopoulos
George D
GD
Nishikawa
Shin-Ichi
S
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D042683:Angiopoietin-1; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta