Thursday, April 25, 2024 4/25/2024

Endothelial dependent mechanisms of lymphatic dysfunction in metabolic syndrome and type-2 diabetes associated with obesity

Award Number: R00HL141143
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Obesity and type-2 diabetes are both considered major risk factors for the development of multiple cardiovascular diseases worldwide. In the US alone, about 36% of the adult population are obese and over 25 million suffer from diabetes. Importantly, the prevalence of type-2 diabetes has been shown to dramatically increase with obesity. Surprisingly, while signs of lymphatic dysfunction have been reported in obesity and diabetes, the mechanisms underlying lymphatic dysfunction are unknown. Efficient lymph transport relies critically on the intrinsic spontaneous contractions of lymphatic muscle cells (LMCs). These contractions are initiated by action potentials that originate at a pacemaking site and then rapidly propagate between the strongly- coupled LMCs. In contrast to arterioles, electrical coupling between lymphatic endothelial cells (LECs) and LMCs through MEJs (myoendothelial junctions) appears to be quite limited; while this may be essential for the focal generation of pacemaking signals, preventing leak of depolarizing current into the endothelium, the idea has not been investigated. Thus, it is completely unknown whether there are any conducted signals in the lymphatic endothelium that can regulate LMC contractility and to what extent heterocellular cross-talk between LECs and LMCs plays a role in lymphatic function. The preliminary data obtained for this proposal show that: 1) signals can be conducted as Ca2+ waves in the lymphatic endothelium, and these waves can regulate the contractile function of LMCs; 2) in obese mice, the spontaneous contractions of isolated lymphatic vessels are impaired (i.e. decreased ejection fraction); 3) the serine protease inhibitor PAI-1, which regulates the formation of vascular MEJs, is an important biomarker for metabolic syndrome, diabetes, and obesity and is upregulated in lymphatic vessels from obese mice compared to those from control healthy mice; and 4) genetic overexpression of PAI-1 (tgPAI-1) in non-obese mice results in lymphatic vessels with impaired contractility, while vessels from age- matched PAI-1 KO mice (PAI-1-/-) show improved lymphatic function. These results suggest novel endothelium- dependent mechanisms through which lymphatic contractions can be regulated, associate obesity with lymphatic contractile dysfunction, point to a novel, critical role for PAI-1 in regulating lymphatic function, and suggest its potential use as therapeutic target to ameliorate lymphatic dysfunction associated with obesity. Therefore, the hypotheses to be tested are: a) Conducted signals in the lymphatic endothelium can regulate LMC contractility through either direct LEC-LMC coupling via MEJs and/or diffusion of released factors; b) increased levels of PAI- 1 result in abnormal cellular interactions, upregulating the formation of MEJs; c) PAI-1 upregulation associated with obesity results in impaired lymphatic function through endothelium-dependent mechanisms; and, d) PAI-1 inhibition can ameliorate lymphatic function in obesity. The studies here proposed and their outcome will expand our understanding on the pathophysiological mechanisms leading to lymphatic dysfunction in metabolic syndrome and diabetes associated with obesity.


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 = -$89,084 )
2024	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	5	1/29/2024	NON-COMPETING CONTINUATION	-$89,084
														Subtotal = -$89,084

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	5	4/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $248,654 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	5	7/1/2022	NON-COMPETING CONTINUATION	$248,654
														Subtotal = $248,654

Issue Date FY: 2021 ( Subtotal = $337,899 )
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	001	4	6/25/2021	NON-COMPETING CONTINUATION	$248,815
2021	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	3	6/18/2021	EXTENSION WITH OR WITHOUT FUNDS	$89,084
														Subtotal = $337,899

Issue Date FY: 2020 ( Subtotal = $248,819 )
2020	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	3	6/22/2020	EXTENSION WITH OR WITHOUT FUNDS	$248,819
														Subtotal = $248,819

Grand Total All Awards = $746,288

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Endothelial dependent mechanisms of lymphatic dysfunction in metabolic syndrome and type-2 diabetes associated with obesity

Award Number: R00HL141143

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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