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Investigating the requirement and regulation of vascular progenitors derived from the Second Heart Field in Pharyngeal Arch Artery development

Award Number: F31HL150949
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY The improper formation or remodeling of the Pharyngeal Arch Arteries (PAAs) are among some of the most severe and life-threatening forms of congenital heart disease, such as those seen in patients with DiGeorge Syndrome. We have previously shown that the PAA endothelium originates from a subpopulation of mesodermal progenitors termed the Second Heart Field (SHF). In addition, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), an RTK which is required for vascular development is highly expressed in these SHF progenitors as they contribute the PAAs. However, to what extent SHF-derived ECs are required for PAA formation, and the mechanisms which regulate the contribution of SHF progenitors to PAAs remains unclear. To address this, we developed a mouse model to conditionally ablate VEGFR2 from the SHF by crossing VEGFR2GFP/+;Isl1Cre/+ and VEGFR2f/f;Rosa26mTmG/mTmG, with the initial hypothesis that the loss of VEGFR2 from SHF vascular progenitors would lead to the absence of PAAs. Unexpectedly, we saw VEGFR2-positive endothelium in VEGFR2GFP/f;Isl1Cre/+ mutant embryos in which VEGFR2 is deleted in the SHF. However, pharyngeal endothelium in these mutants was hypoplastic and disorganized in comparison to control embryos. The use of the Cre reporter Rosa26mTmG demonstrated that these VEGFR2-positive ECs are not of SHF origin but instead, are from another progenitor source, suggesting a possible role for endothelial compensation. Interestingly, embryos heterozygous for VEGFR2 in the SHF lineage showed an impediment in SHF progenitor contribution, in addition to the disorganized and irregular phenotype seen in the knockout embryos, suggesting a possible haploinsufficiency of VEGFR2 in the SHF. Thus, we hypothesize that the SHF contains vascular progenitors essential for proper formation and remodeling of the PAAs. Further, we hypothesize that endothelial cell (EC) progenitors from pre-existing vasculature contributes to the PAAs when SHF contribution is attenuated. Here, we propose to test these hypotheses by addressing the following specific aims: 1) To determine the requirement and mechanisms regulating SHF-derived EC contribution in PAA development; 2) To identify the EC progenitor source(s) that contribute to PAA development when SHF-derived EC contribution is compromised; 3) To determine mechanism(s) that regulate the compensation of PAA ECs when SHF-derived EC contribution is compromised. We will utilize conditional knockout mouse models and immunohistochemistry to fate map and identify the requirement of SHF vascular progenitors in PAA development, and to identify the sources of the non- SHF-derived ECs in the PAAs of embryos null for VEGFR2 in the SHF. Furthermore, we will use a combination of immunohistochemistry and in situ hybridization to provide insight on the mechanisms regulating these vascular progenitors in PAA development. Elucidating sources and mechanisms that drive PAA formation will lead to a better understanding of CHD etiology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$19,472 )
2024	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	3	1/29/2024	NON-COMPETING CONTINUATION	-$19,472
														Subtotal = -$19,472

Issue Date FY: 2022 ( Subtotal = $40,959 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	3	6/30/2022	NON-COMPETING CONTINUATION	$716
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	3	3/29/2022	NON-COMPETING CONTINUATION	$40,243
														Subtotal = $40,959

Issue Date FY: 2021 ( Subtotal = $40,243 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	2	4/8/2021	NON-COMPETING CONTINUATION	$40,243
														Subtotal = $40,243

Issue Date FY: 2020 ( Subtotal = $39,727 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	1	3/1/2020	NEW	$39,727
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	1	3/1/2020	NEW	$0
														Subtotal = $39,727

Grand Total All Awards = $101,457

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Investigating the requirement and regulation of vascular progenitors derived from the Second Heart Field in Pharyngeal Arch Artery development

Award Number: F31HL150949

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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