Abstract 21449: Control of Hif1 and Hif2 in Smooth Muscle is Crucial for Normal Development and Survival
Objective: To investigate the role of the VHL-HIF1-HIF2 axis in smooth muscle.
Methods: VHL, HIF1alpha, and HIF2alpha floxed allele mice in a C57BL6 background were crossed with SM22alpha-Cre mice to create single, and double gene deletion offspring. Live-births and timed-matings were evaluated to determine embryonic lethality, and embryos were examined morphometrically, histologically, by fetal angiography, and by immunostaining at separate developmental stages.
Results: Deletion of VHL in smooth muscle resulted in embryonic lethality, and no live births of this genotype were noted in over 60 litters. Timed-matings revealed embryonic lethality at E14.5–15.5, and over 80% of VHL−/− embryos demonstrated severe gastroschisis. Concomitant deletion of VHL and HIF1alpha in smooth muscle rescued the gastroschisis, and extended fetal development to E16.5–17.5, but the genotype remained developmentally lethal. In addition, this genotype was associated with a intermittent ectopia cordis, another midline defect. Double knockouts of VHL and HIF2a rescued the midline defects and the embryonic lethality. Histological and immunohistochemical examination of the embryos revealed no apparent differences in vascular density between genotypes, but revealed variable differences in the deposition of fibronectin, and evidence of vascular leak in SMC-VHL−/− mice. Micro-CT angiography revealed gross differences in vascular perfusion in the SMC-VHL−/− mice, despite no gross morphological or histologically apparent etiology. Vascular segments from the SMC-VHL−/− mice demonstrated increased susceptibility to vascular spasm, suggesting that altered vascular reactivity contributes to the embryonic lethality.
Conclusions: Control of HIF1 and HIF2 activity in smooth muscle is crucial for normal development and viability, with HIF2 predominating.
- © 2010 by American Heart Association, Inc.