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VEGF Gene Delivery In The Primate To Prevent Defective Spiral Artery Remodeling And Maternal Vascular Dysfunction

Award Number: R01HD093070
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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VEGF Gene Delivery In The Primate To Prevent Defective Spiral Artery Remodeling And Maternal Vascular Dysfunction - PROJECT SUMMARY/ABSTRACT During early human pregnancy, placental extravillous trophoblasts invade and remodel the uterine spiral arteries into distensible low-resistance vessels to promote placental perfusion and thus fetal development. A defect in uterine spiral artery remodeling (SAR) is the primum movens step that underpins adverse human pregnancy, particularly preeclampsia, which leads to systemic vascular dysfunction in and increased morbidity and mortality of the mother and offspring. However, there are no experimental primate models of defective SAR, noninvasive methods to detect the defect in SAR in early pregnancy or therapeutic modalities to prevent the maternal and offspring vascular dysfunction. We established a model of impaired SAR by slightly elevating estradiol in the first trimester of baboon pregnancy. This model is characterized by a decrease in extravillous trophoblast vascular endothelial growth factor (VEGF) expression, increase in placental expression and maternal serum levels of the soluble fms-like tyrosine kinase-1 receptor (sFlt-1) that suppresses VEGF bioavailability, maternal (published) and offspring (preliminary) vascular dysfunction, reduced fetal growth and increased incidence of perinatal demise. We also employed B- flow/spatio-temporal image correlation (STIC) M-mode ultrasonography to detect SAR impairment in early pregnancy. Importantly, ultrasound- mediated/microbubble-facilitated gene delivery (UMGD) of VEGF to the placental basal plate of estradiol- treated baboons early in pregnancy abolished the defect in SAR. However, it has not been established whether reversing the defect in SAR by UMGD of VEGF will prevent maternal and offspring vascular dysfunction. The foundation built upon this primate model during the recent R01 HD 93070 project period, provides a highly unique opportunity to test the novel hypothesis that VEGF gene delivery to restore SAR will prevent vascular dysfunction in the mother, fetus and offspring. Baboons will be untreated, treated with estradiol to suppress SAR or treated with estradiol and UMGD of VEGF to reverse SAR impairment. Normal and defective SAR will be determined by B-flow/STIC M-mode ultrasonography in the first trimester. Vascular function will be quantified in the mothers and fetuses at midgestation and near term and the offspring at 0.5, 1 and 4 years after birth. Systemic microvessel endothelial function will be ascertained by quantifying microvessel endothelial cell-specific nitric oxide synthase (eNOS) and VEGF mRNAs by RT-PCR and protein levels by proximity ligation assay and capillary density by image analysis. Microvessel endothelial function will be assessed in mothers and offspring by brachial artery flow-mediated dilation and microvessel flow by contrast-enhanced ultrasonography (CEU) before and after hyperemia induced shear-stress and acetylcholine with/without L-name administration. This study will be highly significant in establishing a therapeutic modality to prevent the maternal and infant vascular dysfunction that is caused by improper SAR.


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: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	7	12/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $663,998 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	7	4/4/2025	NON-COMPETING CONTINUATION	$663,998
														Subtotal = $663,998

Issue Date FY: 2024 ( Subtotal = $678,785 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	001	6	7/30/2024	COMPETING CONTINUATION	$678,785
2024	2021	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	5	1/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $678,785

Issue Date FY: 2021 ( Subtotal = $615,555 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	5	6/24/2021	NON-COMPETING CONTINUATION	$615,555
														Subtotal = $615,555

Issue Date FY: 2020 ( Subtotal = $628,119 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	4	6/11/2020	NON-COMPETING CONTINUATION	$628,119
														Subtotal = $628,119

Issue Date FY: 2019 ( Subtotal = $628,119 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	3	6/13/2019	NON-COMPETING CONTINUATION	$628,119
														Subtotal = $628,119

Issue Date FY: 2018 ( Subtotal = $628,119 )
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	6/19/2018	NON-COMPETING CONTINUATION	$628,119
														Subtotal = $628,119

Issue Date FY: 2017 ( Subtotal = $640,210 )
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	9/8/2017	NEW	$640,210
														Subtotal = $640,210

Grand Total All Awards = $4,482,905

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VEGF Gene Delivery In The Primate To Prevent Defective Spiral Artery Remodeling And Maternal Vascular Dysfunction

Award Number: R01HD093070

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/08/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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