# The role of Tie2 signaling in Aortic Valve Remodeling > **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $693,128 ## Abstract Abnormal valve development contributes to many common congenital heart malformations. Developmental signaling events that regulate early valve formation have been studied extensively, however, the mechanisms that underlie latter stages of remodeling to mature valves remain poorly understood. We have recently identified a critical time point at the early stage of semilunar valve remodeling that is fundamental for normal aortic valve formation and have also identified a unique endocardial signaling axis, TIE2-PI3K/AKT- FOXO1, that plays a pivotal role in orchestrating this early remodeling process. Therefore, we propose to 1) Delineate the unique roles of TIE2 signaling in heart valve remodeling in vivo. We will utilize our newly developed inducible endocardial Cell (EC) specific Nfatc1CreERT2 line, pan-endocardial (Nfatc1Cre) line, and valvular endocardial specific (Nfatc1enCre) line, to generate valvular EC-specific Tie2 conditional knockout (ko) models. PostnMCM will likewise be used to generate valvular mesenchymal cell ko mutants. We will thoroughly examine the cardiac phenotypes of these conditional mutant mice and determine the direct effectors of endocardial TIE2 signaling in heart valve remodeling. 2) Define the role of the TIE2-PI3K/AKT-FOXO1 signaling during semilunar valve remodeling in vivo. We will generate an EC overexpression of a gain-of- function FOXO1 mouse line (FOXO1CA). We will also generate Tie2 and FoxO1 double knock out mutants via utilization of Nfatc1CreERT2 and Tie2 and FoxO1 floxed alleles and EC overexpression of a gain-of-function PI3K mouse line (PIK3CAH1047R) via Nfatc1Cre and Nfatc1enCre, respectively. The resultant mutant mice will be thoroughly analyzed to determine which components of the cardiac valve defects seen in Tie2-icko and Nfatc1enCre;PIK3CAH1047R mutant mice are phenocopied or rescued, thus defining the specific roles of TIE2- PI3K/AKT-FOXO1 signaling in valve formation. 3) Identify additional down-stream targets of TIE2 activation that regulate heart valve remodeling. To validate and reinforce the TIE2-FOXO1 linear pathway proposed based on in vivo studies, we will analyze candidate gene/protein expression of cultured endothelial cells exposed to CAng1, a potent Angpt1 variant agonist, and PI3K inhibitor (LY294002) in the presence or absence of Tie2. In addition, we will use bulk RNAseq of cultured cells and scRNAseq of outflow tracts harvested from control and inducible endocardial Tie2 ko embryos to identify and characterize additional TIE2- dependent signaling pathways required for semilunar valve development. These studies will provide the first characterization of the critical period of aortic valve remodeling immediately following EMT. This work will also elucidate a uniqe endocardial signaling mechanism (namely, the TIE2-FOXO1 axis) that modulates remodeling in cardiac valve formation. These studies are essential to advance our understanding of normal cardiac valve ontogeny and will be foundati... ## Key facts - **NIH application ID:** 10872013 - **Project number:** 1R01HL173766-01 - **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER - **Principal Investigator:** H Scott Baldwin - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $693,128 - **Award type:** 1 - **Project period:** 2024-08-10 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10872013 ## Citation > US National Institutes of Health, RePORTER application 10872013, The role of Tie2 signaling in Aortic Valve Remodeling (1R01HL173766-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10872013. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*