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Mechanical Control of Coronary Angiogenesis in Myocardial Adaptation to Ischemia

Award Number: R01HL148585
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mechanical Control of Coronary Angiogenesis in Myocardial Adaptation to Ischemia - Inadequate capillary growth; inadequate perfusion and the consequential ischemia can initiate the sequelae of events causing the progression from an initial compensatory left ventricular hypertrophy (LVH) (in response to hemodynamic challenge) to maladaptation leading to heart failure. Although pro-angiogenic strategies such as delivery of growth factors and gene therapy are promising, there are limitations and concerns, including delivery modalities, uncontrolled angiogenesis, limited half-life of growth factors, and effects on other organs. Our proposal takes an alternative approach to test the hypothesis that mechanical forces in the hypertrophied ventricle adversely affect coronary angiogenesis during heart failure. The central objective of this proposal is to demonstrate that mechanical forces impede coronary angiogenesis during ischemia and hypertrophy. Our objective is based on the counterintuitive observations that a) endothelial cells (EC) null for a mechanosensitive ion channel, Transient Receptor Potential Vanilloid-4 (TRPV4) exhibited increased proliferation, migration, Rho activity, and tube formation compared to wild type EC b) both ex vivo (aortic sprouting) and in vivo (Matrigel, tumor and retinal) angiogenesis is enhanced in TRPV4KO mice compared WT and c) global (TRPV4KO) or endothelial specific (TRPV4ECKO) TRPV4 knockout mice exhibited improved cardiac function that correlated with reduced cardiac fibrosis and increased coronary angiogenesis compared to WTs subjected to LVH induced by either myocardial infarction (MI) or pressure-overload (transverse aortic constriction (TAC). These findings suggest that mechanical forces exert restraint on angiogenesis and uncoupling this mechanical effect (endothelial TRPV4 mechanotransduction) restores angiogenesis and cardiac function. Thus, our working hypothesis is that TRPV4 channels regulate angiogenesis via modulation of Rho activity that regulates EC contraction and VEGFR2 trafficking via YAP and that the absence of TRPV4 increases angiogenesis in myocardium and protects heart from ischemia- or pressure-overload- induced cardiac injury. We will test this hypothesis in the following specific aims 1) To identify the structural domains within TRPV4 that are required for the modulation of endothelial mechanosensitivity, Rho activation and angiogenesis 2) To define the molecular mechanism(s) by which TRPV4 integrates Rho/YAP and VEGF signaling in coronary angiogenesis and 3) To ascertain the functional significance of endothelial TRPV4 and to target TRPV4 with a small molecule inhibitor to induce angiogenesis in the myocardium. To accomplish this, we propose to use an innovative combination of advanced in vitro and in vivo techniques such as FRET, contrast echocardiography, multi-photon microscopy, engineered ECM gels that mimic stiffness of heart, endothelial-specific TRPV4KO mice (conventional and inducible) in conjunction with MI and TAC models. Our proposed studies will provide insights into the mechanism by which mechanical forces regulate coronary angiogenesis and may open entirely new avenues for development of therapeutics for angiogenesis.


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	2022	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	000	4	2/18/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	000	4	6/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $476,065 )
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	002	4	6/21/2022	NON-COMPETING CONTINUATION	$476,065
2022	2021	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	001	3	11/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$395,482
2022	2020	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Cardiovascular Diseases Research	000	2	11/25/2021	NON-COMPETING CONTINUATION	-$395,482
														Subtotal = $476,065

Issue Date FY: 2021 ( Subtotal = $476,065 )
2021	2021	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	002	3	7/19/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2021	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	001	3	7/7/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$476,065
2021	2020	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Cardiovascular Diseases Research	000	2	7/6/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $476,065

Issue Date FY: 2020 ( Subtotal = $437,160 )
2020	2020	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Cardiovascular Diseases Research	000	2	8/20/2020	NON-COMPETING CONTINUATION	$437,160
														Subtotal = $437,160

Issue Date FY: 2019 ( Subtotal = $451,160 )
2019	2019	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Cardiovascular Diseases Research	000	1	9/17/2019	NEW	$451,160
														Subtotal = $451,160

Grand Total All Awards = $1,840,450

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Mechanical Control of Coronary Angiogenesis in Myocardial Adaptation to Ischemia

Award Number: R01HL148585

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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