Venezia Podesta
Pronouns: She/Her
Research Mentor(s): Nathaniel Lartey
Research Mentor School/College/Department: Microbiology and Immunology / Medicine
Program:
Authors: Venezia Podesta, Nathaniel Lartey, Philip King
Session: Session 4: 1:40 pm – 2:30 pm
Poster: 54
Abstract
Mutations in Ephrin receptor B4 (EPHB4) and Ras p21 protein activator 1 (RASA1) genes are the causes of capillary malformation-arteriovenous malformation (CM-AVM) in humans. CM-AVM is an autosomal-dominant vascular anomaly characterized by cutaneous CM and fast-flow vascular lesions that can be life-threatening depending on location. Deficiency of RASA1 in mice leads to embryonic lethality at embryonic day E10.5. Induced-loss of RASA1 in embryos leads to blocked developmental angiogenesis, a process where primitive vascular plexus is remodeled into hierarchical arterio-capillary-venous networks. Mechanistically, there was impaired export of a basement membrane-stabilizing protein, collagen IV, leading to endoplasmic stress-mediated endothelial cell death and severe hemorrhage. Also there was increased expression levels of collagen IV modifiers such as the lysyl hydroxylase, Plod2. Hence we hypothesize that the heterozygous loss of PLOD2 will avert the over-modification of collagen IV and ensure proper protein folding and export in RASA1-deficient embryos during development. To this end, we generated RASA1 and PLOD2 floxed mice. We interbred these mice to produce females that would be RASA1 fl/fl, PLOD2 fl/+ to be used for the appropriate timed-matings with RASA1 fl/fl Cdh5-ERT2-Cre male mice. Notably, heterozygous loss of PLOD2 appears to partially rescue the vascular phenotype associated with Rasa1 loss in embryos. Additionally, heterozygous loss of PLOD2 in induced RASA1-deficient mice ameliorates endothelial cell death. Thus, our preliminary results suggest that targeting PLOD2 could be explored as a promising therapeutic strategy for RASA1-induced vascular anomalies such as CM-AVM.
