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Estrogen Regulation of Fetal Microvessel Development During Primate Pregnancy: Impact on Insulin Sensitivity in Offspring

Award Number: R01DK120513
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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We recently showed that offspring delivered to estrogen (E2)-suppressed baboons exhibited insulin resistance, glucose intolerance, and a deficit in first phase insulin secretion, steps that progress to type 2 diabetes mellitus (T2DM). However, the mechanism(s) underpinning this E2 regulated event are unknown. The microvessel (MV) unit (i.e. arterioles and associated capillaries [cap]) has a fundamentally important role in insulin action by enabling insulin and glucose delivery to target tissue, notably skeletal muscle (SM). An extensive MV network forms within insulin target tissues during fetal development, however, little is known about the regulation of this critically important developmental process in the fetus. Angiogenesis is foundational for expansion of the cap network during fetal development and vascular endothelial growth factor-A (VEGF) is a predominant regulator of angiogenesis in SM. Therefore, the over-arching highly novel concept of this “developmental origin of health and disease” study is that E2 in utero promotes SM MV development in the fetus and consequently formation of an extensive MV network critical for the delivery of insulin and glucose to and thus insulin action and glucose homeostasis within SM in the offspring. In Aim 1, we will test the hypothesis that E2 promotes SM MV morphological and functional development in the baboon fetus as an essential step leading to insulin sensitivity in the offspring. SM VEGF expression, cap density and MV maturation and morphology will be quantified in the fetus at mid (day 100) and late (days 165-175; term = 184 days) gestation and in offspring at 2, 3 and 4 years of age delivered to baboons untreated or in which E2 production/levels have been suppressed by maternal administration of the aromatase inhibitor letrozole and restored by letrozole plus E2. SM vascular function will be assessed by brachial artery flow-mediated dilation and by cap flow, as quantified by contrast-enhanced ultrasound/microbubble technology, before/during vasochallenge of offspring delivered to E2-deprived/-replenished baboons. Aim 2 will determine the mechanisms by which E2 acts to promote SM angiogenesis in the fetus as established in Aim 1. We will test the hypothesis that E2 rapidly stimulates SM VEGF expression, cap endothelial cell (EC) tight junction (TJ)/adherens junction (AJ) breakdown, and cap EC proliferation as early steps in angiogenesis on day 165 of gestation 0-24 h after an iv bolus injection of E2 to fetuses of letrozole-treated baboons. The proposed study is clinically significant since preterm birth, aromatase mutation, steroid sulfatase deficiency, estrogen receptor null mutation, and maternal/fetal exposure to endocrine disruptors, which curtail exposure of the fetus to the normal elevation in or action of E2, are associated with increased incidence of insulin resistance/T2DM in human offspring. Establishing the importance of E2 to fetal MV development and onset of insulin sensitivity in primate offspring provides a basis for therapeutic application to the human.


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 = $634,187 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/5/2024	NON-COMPETING CONTINUATION	$634,187
														Subtotal = $634,187

Issue Date FY: 2023 ( Subtotal = $704,651 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/28/2023	NON-COMPETING CONTINUATION	$704,651
														Subtotal = $704,651

Issue Date FY: 2022 ( Subtotal = $704,651 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/7/2022	NON-COMPETING CONTINUATION	$70,464
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/20/2022	NON-COMPETING CONTINUATION	$634,187
														Subtotal = $704,651

Issue Date FY: 2021 ( Subtotal = $704,829 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/12/2021	NON-COMPETING CONTINUATION	$704,829
														Subtotal = $704,829

Issue Date FY: 2020 ( Subtotal = $687,568 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/22/2020	NEW	$687,568
														Subtotal = $687,568

Grand Total All Awards = $3,435,886

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Estrogen Regulation of Fetal Microvessel Development During Primate Pregnancy: Impact on Insulin Sensitivity in Offspring

Award Number: R01DK120513

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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