The suppression of Tbdn-1 expression in mouse endothelium resulted in several pathologic features observed in human proliferative retinopathies including retinal neovascularization, preretinal fibrovascular proliferation, and retina–lens adhesions. Manipulation of specific protein expression has been demonstrated to induce retinal neovascularization in vivo. Previously described models of neovascular retinopathy include overexpression of growth factors. Transgenic mouse models of VEGF overexpression in the retina have been sufficient to cause retinal neovascularization and tractional retinal detachment.
23 24 Transgenic mice overexpressing PDGF-B in photoreceptors soon after birth undergo development of retinal lesions harboring glial, endothelial, and pericyte elements, leading to retinal detachment.
25 However, in contrast to Tbdn-1, the effects of endothelial ablation of PDGF-B are not restricted to the ocular vascular bed,
26 whereas VEGF, an endothelium-specific growth factor, can affect the vasculature of most tissues.
27 28 29 In the adult, high levels of Tbdn-1 expression are restricted to specialized vasculature, including ocular blood vessels, bone marrow capillaries, atrial endocardium, and blood vessels of regressing ovarian follicles.
16 17 The restriction of pathologic changes to the retina and choroid in Dox-induced
TIE2/
rtTA/
Enh-TRE/
ASTBDN-1 mice indicates that the effects resulting from Tbdn-1 suppression in endothelia is highly specific to retinal and choroidal blood vessels. The lack of disease in other adult tissues might be explained either by the absence of Tbdn-1 expression in the corresponding vascular bed,
16 17 by the absence of a critical binding partner or cofactor important for mediating Tbdn-1 activity in the given tissue, or by presence of a Tbdn-1 homologue that may act in a compensatory manner during Tbdn-1 suppression. Such possible binding partners may include mammalian orthologues of the yeast ARD1 acetyltransferase.
30 31 The Tbdn-1 homologue NAT1 protein, which is expressed in mammalian brain tissue and may play a role in regulating neural responses to cell signaling through the
N-methyl-
d-aspartate pathway,
30 may function in a redundant manner in brain in the absence of Tbdn-1.