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Role of endothelial Sox17 in EC-SMC crosstalk and homeostatic regulation of blood vessel adaption to arterial hemodynamics

Award Number: R01HL162908
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Arteries and veins play different roles in human physiology and vascular diseases. Notably, arterial and venous endothelial cells (ECs) demonstrate distinct molecular profiles. The establishment of such molecular distinction is orchestrated by series of transcriptional programs, which have been well studied in developmental biology. However, how these EC transcriptional programs control adult blood vessel structure and function, and how to translate this knowledge into clinical application such as vein or tissue engineered graft adaptation is under- explored. To address this question, we examined the transcription profile of arterial vs. venous ECs in adult blood vessels and have identified several key transcription factors that are differentially expressed in arterial vs. venous ECs. Among them, Sox13 and Sox17 are highly expressed in adult arterial ECs but not in venous ECs. Our preliminary studies demonstrate that over-expressing Sox17 in venous ECs reconstitutes all the known arterial markers, suggesting Sox17 is a key regulator of adult arterial EC phenotypes. Importantly, Sox17 induces the expression of multiple families of molecules (Notch, Ephrin, Connexins, PDGF) that may confer signals from ECs to smooth muscle cells (SMCs) to regulate SMC phenotypes in blood vessels. EC Sox17 also promoted SMC contractile phenotype in EC-SMC co-culture and graft remodeling model. On the other hand, over-expressing Sox13 in ECs facilitates the recruitment of SMCs toward blood vessels. Based on these encouraging preliminary data, we hypothesize that endothelial Sox13/17 play synergistic roles in the homeostatic regulation of adult artery functions by maintaining adult arterial EC phenotype and engaging EC- SMC crosstalk. To test this hypothesis, we will investigate how the endothelial Sox13/17 regulates EC and SMC phenotypes and their role in blood vessel structures and functions using in vitro bioengineered models as well as in vivo animal models.


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 = $571,838 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	5/23/2024	NON-COMPETING CONTINUATION	$571,838
														Subtotal = $571,838

Issue Date FY: 2023 ( Subtotal = $580,158 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	6/6/2023	NON-COMPETING CONTINUATION	$580,158
														Subtotal = $580,158

Issue Date FY: 2022 ( Subtotal = $589,383 )
2022	2022	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	5/27/2022	NEW	$589,383
														Subtotal = $589,383

Grand Total All Awards = $1,741,379

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Role of endothelial Sox17 in EC-SMC crosstalk and homeostatic regulation of blood vessel adaption to arterial hemodynamics

Award Number: R01HL162908

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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