Tuesday, February 4, 2025 2/4/2025

Endothelial Cell to Mesenchymal Cell Transitions Play a Critical Biological Sex- and Aging-Dependent Role in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap

Award Number: R01HL156849
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain poorly understood. Recent studies from our lab (2021 Nature Metabolism) showed that smooth muscle cell (SMC) conditional knockout (KO) of the platelet-derived growth factor receptor-β (PDGFRβ) in ApoE-/- mice was associated with nearly complete failure of SMC to invest into lesions or the fibrous cap. However, despite nearly complete absence of SMC in lesions of SMC PDGFRβ KO mice, surprisingly we observed no changes in lesion size or indices of plaque stability, including the thickness of the ACTA2+ fibrous cap, following 18 weeks of Western diet (WD). Further studies showed that: 1) contrary to dogma that Acta2+ fibrous cap cells are derived almost exclusively from SMC, we found they account for only 60-75% of ACTA2+ cells in advanced ApoE-/- brachiocephalic (BCA) or human coronary artery (CA) lesions with the remainder coming from endothelial cell (EC)-to-mesenchymal-to-myofibroblast transitions (EndoMT-MFT, 15-20%) and macrophage-to-myofibroblast transitions (MMFT, 10-15%); 2) loss of SMC investment into lesions with SMC PDGFR? KO or bone marrow transplantation (BMT) was associated with a 2-3 fold increase in EndoMT-MFT and MMFT; 3) increased EndoMT-MFT, and MMFT did not sustain indices of stability when WD feeding was extended to 26 weeks suggesting qualitative differences in the ability of fibrous cap cells to sustain lesion stability depending on their origin; 4) the contribution of EC to the ACTA2+ fibrous cap increased with lesion regression by feeding mice 18 weeks of WD followed by 12 weeks of chow diet; and 5) female but not male mice exhibit IL1R1-dependent EndoMT. Studies herein will test the hypothesis that the contribution of EC to the ACTA2+ fibrous cap increases with lethal irradiation-BMT, SMC PDGFRβ KO, aging, female sex, and/or plaque regression resulting in: 1) increased EC proliferation and replicative senescence; 2) loss of EC integrity and/or reduced anti- thrombotic properties; and 3) increased susceptibility to plaque erosion or rupture. Aim 1 will determine if the marked increase in the contribution of EndoMT-MFT to the ACTA2+ fibrous cap following lethal irradiation-BMT, SMC PDGFR? KO, or with plaque regression is associated with increased proliferation, clonal expansion, replicative senescence, and/or dysfunction of EC. Aim 2 will determine if treatment of our SMC- or EC-lineage tracing ApoE-/- or our novel Myh11-CreERT2/Rosa-eYFP/SR-BIΔCT/ΔCT/LDLR- (ΔCT) mice with advanced BCA and CA lesions with senolytic drugs is associated with beneficial changes in indices of plaque stability, improved survival, reduced MI or stroke, reduced dependence on EndoMT-MFT for maintenance of the ACTA2+ fibrous cap, and/or improved EC integrity and/or function. All aims include human validation studies on stable versus high risk carotid endarterectomy samples, and assessment of sex-dependent determinants of late-stage lesion pathogenesis. The proposed studies will provide novel insights regarding mechanisms that regulate the cellular and extracellular matrix (ECM) composition of the fibrous cap and may lead to development of novel therapeutic approaches for enhancing plaque stability.


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: 2025 ( Subtotal = $713,630 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	11/29/2024	NON-COMPETING CONTINUATION	$713,630
														Subtotal = $713,630

Issue Date FY: 2024 ( Subtotal = $777,063 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	3	12/18/2023	NON-COMPETING CONTINUATION	$713,630
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	3	6/8/2024	NON-COMPETING CONTINUATION	$63,433
														Subtotal = $777,063

Issue Date FY: 2023 ( Subtotal = $792,922 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	2	12/16/2022	NON-COMPETING CONTINUATION	$713,630
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	002	2	3/20/2023	NON-COMPETING CONTINUATION	$0
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$79,292
														Subtotal = $792,922

Issue Date FY: 2022 ( Subtotal = $792,922 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	12/17/2021	NEW	$792,922
														Subtotal = $792,922

Grand Total All Awards = $3,076,537

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Endothelial Cell to Mesenchymal Cell Transitions Play a Critical Biological Sex- and Aging-Dependent Role in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap

Award Number: R01HL156849

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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