Sunday, December 21, 2025 12/21/2025

Endothelial Regulation of Vascular Calcification

Award Number: R01HL158053
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Endothelial Regulation of Vascular Calcification - PROJECT SUMMARY: Vascular calcification (VC) frequently complicates cardiovascular disease. It increases the morbidity and mortality and constitutes a significant obstacle in interventions and surgeries. The vascular endothelium plays an important role in VC. The intimal (luminal) endothelial cells (ECs) contribute to VC by providing osteoprogenitor cells through endothelial-mesenchymal transitions (EndMTs). The adventitial ECs are known to contribute to neo-angiogenesis in diseased vascular wall, but it is unknown whether such ECs support VC and what defines them. A subset of ECs with high expression of the EC marker CD31 and the glycoprotein Endomucin (Emcn) has been found in bone to support bone formation. It is possible that adventitial or other peripheral ECs are recruited to diseased areas to promote calcification. Preliminary experiments, using the Matrix Gla Protein null (Mgp-/-) mouse as a VC model, showed extensive EC involvement in the calcified aorta. We identified two subtypes of ECs in the adventitial vs. the intimal endothelium (referred to as a-ECs and i- ECs). The a-ECs were CD31+Emcm+ and correlated with the severity of the VC, whereas the i-ECs were CD31+Emcn-. The two ECs had distinct transcriptional profiles with stem cell and osteogenic markers in the i- ECs vs. enhanced Notch expression in the a-ECs. Endothelial deletion of Notch1 reduced the a-ECs and limited VC while promoting cartilage formation and survival in the Mgp-/- mice. The bone transcription factor Osterix was expressed in both types of ECs. We hypothesize that a-ECs are distinct from i-ECs, recruited to nascent VC, and susceptible to Notch disruption. We also hypothesize that Osterix is protective of EC lineage. In Aim 1, we will characterize the a-ECs (CD31+Emcn+) and compare to the i-ECs (CD31+Emcn-) in the Mgp-/- model, and correlate with severity of VC and marker expression. We will identify unique markers for the respective ECs, with comparison to bone, using transcriptional profiles from single cell RNA sequencing (scRNAseq). We will test the concept that angiogenesis is required for VC using angiogenic inhibitors. In Aim 2, we will determine the effect of loss or gain of endothelial Notch signaling on the EC subtypes and VC. We will examine the distribution of Notch components in relation to VC, and generate Mgp-/- mice with endothelial- specific loss of Notch1 or the Notch receptor inactivator Fbxw7. We will use the mice to determine the effect on the appearance of the endothelial subtypes, calcification and transcriptional profiles by scRNAseq. We will also apply loss and gain of Notch to ECs in vitro and identify novel Notch targets and networks. In Aim 3, we will determine if Osterix helps maintain EC lineage or promotes calcification in vitro and in vivo using human aortic ECs and inducible endothelial-specific Osterix gene deletion in Mgp-/- mice. We will compare the transcriptional profiles of ECs with and without Osterix by scRNAseq in order to clarify the effect on EC lineage, a-ECs vc. I- ECs, and involved signaling networks. Our results may have a significant impact on the field of VC, in particular on the understanding of the endothelial pathology and involvement in VC.


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	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	11/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $540,935 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	12/16/2024	NON-COMPETING CONTINUATION	$486,841
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	4	8/14/2025	NON-COMPETING CONTINUATION	$54,094
														Subtotal = $540,935

Issue Date FY: 2024 ( Subtotal = $530,115 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	3	6/22/2024	NON-COMPETING CONTINUATION	$43,274
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	12/8/2023	NON-COMPETING CONTINUATION	$486,841
														Subtotal = $530,115

Issue Date FY: 2023 ( Subtotal = $540,935 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	3/16/2023	NON-COMPETING CONTINUATION	$540,935
														Subtotal = $540,935

Issue Date FY: 2022 ( Subtotal = $540,935 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	12/15/2021	NEW	$540,935
														Subtotal = $540,935

Grand Total All Awards = $2,152,920

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Endothelial Regulation of Vascular Calcification

Award Number: R01HL158053

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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