Impaired angiogenesis in aminopeptidase N-null mice.
Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports of in vivo inactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APN-null mice. These findings establish that APN-null mice develop normally without physiological alterations and can undergo physiological angiogenesis but show a severely impaired angiogenic response under pathological conditions. Finally, in addition to vascular biology research, APN-null mice may be useful reagents in other medical fields such as malignant, cardiovascular, immunological, or infectious diseases.
Rangel
Roberto
R
Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Sun
Yan
Y
Guzman-Rojas
Liliana
L
Ozawa
Michael G
MG
Sun
Jessica
J
Giordano
Ricardo J
RJ
Van Pelt
Carolyn S
CS
Tinkey
Peggy T
PT
Behringer
Richard R
RR
Sidman
Richard L
RL
Arap
Wadih
W
Pasqualini
Renata
R
D000818:Animals; D018826:CD13 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D018919:Neovascularization, Physiologic; D010641:Phenotype; D012162:Retinal Degeneration / Q000235:genetics
D018826:CD13 Antigens