Purchase this article with an account.
leah owen, Derick Holt, Hironori Uehara, Balamurali Ambati; SAMHD1 is a Novel Regulator of Soluble Flt-1. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2085.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Aberrant angiogenesis is fundamental to numerous ocular pathologies and represents a significant clinical problem. Current therapeutics primarily target vascular endothelial growth factor (VEGF) though with incomplete efficacy. This may be due to the fact that the full complement of disease mechanisms is not addressed, or alternatively that there is a more central “molecular switch” responsible for this pathology. Soluble vascular endothelial growth factor receptor-1 (sFLT1) has emerged as an important endogenous regulator of both physiologic and pathologic angiogenesis in multiple tissues including the eye. sFlt1 is a physiologic splice variant of the full length FLT1 receptor which contains only the ligand binding domain and therefore functions as an endogenous VEGF inhibitor. While sFLT1 plays an important role in physiologic corneal avascularity, molecular pathways important for its production remain incompletely understood.
Genome-wide microarray was performed using murine models of corneal neovascularization expressing a gradient of sFlt1. Corneal samples were assessed from MRL mice which are known to expression supra-physiologic levels of sFlt1 and have avascular corneas, Pax6+/- mice which express low levels of sFlt1 and have spontaneously vascularized corneas, as well as wild-type controls. Candidate genes were identified for which expression correlated significantly with sFlt1 gradient expression. These data were confirmed using real-time PCR. Functional relevance was determined using si-RNA mediated knock-down of candidate regulators in human umbilical vein endothelial cells followed by real-time PCR assessment of sFlt1 expression.
SAMHD1 expression was found to correlate significantly with decreased sFlt1 expression and the presence of corneal neovascularization. These data were confirmed using siRNA mediated knock-down of SAMHD1 which demonstrated increased sFlt1 expression in the presence of SAMHD1 knock-down.
SAMHD1 represents a novel regulator of sFlt1 which is necessary for suppression of sFlt1 expression. The physiologic function of SAMHD1 is unknown, though its SAM domain classically mediates protein interactions and its HD domain is thought to have phosphohydrolase activity. Further work will clarify whether SAMHD1 function is sufficient to mediate sFlt1 suppression and investigate the mechanism of action allowing for SAMHD1 to evolve as a possible therapeutic target in the future.
This PDF is available to Subscribers Only