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SMC macropinocytosis: a novel target in atherosclerotic vascular disease

Award Number: R01HL164792
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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SMC macropinocytosis: a novel target in atherosclerotic vascular disease - Project Summary Atherosclerosis is a leading cause of morbidity and mortality globally. Recently, cell lineage tracing, single-cell RNA sequencing and human genomic studies have been integrated to demonstrate that a) majority of plaque foam cells are of vascular smooth muscle cell (SMC) origin and b) SMC can undergo a fate switch to transitional, multipotential cells that can adopt plaque altering phenotypes. Although these results identify SMC as potential therapeutic targets, most current treatments for atherosclerosis have little direct impact on SMC. The endocytic processes by which SMC take up lipids and become foam cells in the arterial wall are not clearly defined. In addition, the mechanisms underlying SMC phenotypic switching in the arterial wall remain largely unknown. Using a combination of high-resolution imaging, 3D cell reconstruction, and LDL immunolabeling, we have recently demonstrated that foam cells (lineage unknown) in human and murine atherosclerotic plaques internalize LDL via macropinocytosis. Novel preliminary data using SMC lineage tracing identifies SMC subsets performing macropinocytosis in the arterial wall in vivo. Stimulation of macropinocytosis of LDL in SMC promotes dedifferentiation and phenotype switching into plaque-promoting phenotypes in vitro. Further, pharmacological blockade of macropinocytosis using the Na+/H+ exchanger 1 (NHE1) blocker, EIPA, inhibits LDL uptake in atherosclerotic arteries and abrogates atherosclerosis development in multiple murine models of atherosclerosis. Preliminary data also show that the matricellular protein thrombospondin-1 (TSP1) stimulates macropinocytosis via CD47 in SMC, leading to foam cell formation and phenotypic switching, and global Cd47-/- mice are protected from atherosclerosis. Based on these observations, we hypothesize that SMC macropinocytosis drives atherosclerosis through foam cell formation and regulation of SMC phenotypic switching. The hypothesis will be tested via the following specific aims: Aim 1: SMC internalize LDL via macropinocytosis in atherosclerotic arteries. Aim 2: SMC-specific inhibition of macropinocytosis attenuates transdifferentiation of SMC into a plaque- promoting phenotype and inhibits atherosclerosis. Aim 3: TSP1 via CD47 stimulates SMC macropinocytosis, promotes SMC phenotypic switching and contributes to atherosclerosis development. The proposal will employ SMC-specific knockout mice (Nhe1-/-, Cd47-/- and Cd36-/-), primary human and murine aortic SMC, a vascular SMC-restricted Cre driver mouse model (Itga8-CreERT2+/-; mTmG+/-), and other genetic tools to test the hypothesis. Multiple complementary techniques will be used to study SMC macropinocytosis in vitro (pharmacological, genetic, fluorescence/SEM imaging) and in vivo (TEM/IEM microscopy, SMC-specific Nhe1 knockout mice). At their conclusion, the proposed studies will define key mechanism(s) promoting SMC foam cell formation and phenotypic switching and potentially identify new targets for therapeutic interventions of atherosclerosis.


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 = $563,675 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	3	6/26/2025	NON-COMPETING CONTINUATION	$56,367
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	4/21/2025	NON-COMPETING CONTINUATION	$507,308
														Subtotal = $563,675

Issue Date FY: 2024 ( Subtotal = $552,402 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	3/28/2024	NON-COMPETING CONTINUATION	$507,308
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$45,094
														Subtotal = $552,402

Issue Date FY: 2023 ( Subtotal = $563,675 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	5/15/2023	NEW	$563,675
														Subtotal = $563,675

Grand Total All Awards = $1,679,752

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SMC macropinocytosis: a novel target in atherosclerotic vascular disease

Award Number: R01HL164792

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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