# Pathological flow-induced endothelial damage and plaque erosion

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $793,939

## Abstract

Project Summary/Abstract
Atherosclerotic and high-risk plaques including both rupture and erosion are predominantly localized to vessel
wall regions with non-laminar disturbed blood flow (d-flow) and laminar high flow (h-flow). However, the
molecular mechanisms of this pathological flow-induced high-risk plaque remain largely unknown mainly
because of the lack of such high-risk plaque animal models, hence there is an urgent need to correct this gap.
Our long-term goal is to determine how the high-risk plaque is formed by pathological flow. We found that
within 14 days after inducing LATS (large tumor suppressor homolog) 1/2 deletion in tamoxifen-inducible
endothelial cell (EC) specific LATS1homo/LATS2homoknock-out mice (LATS1homo/LATS2homo-EKO), all mice
(28/28) died of severe systemic edema, accompanied by massive EC apoptosis. Next we generated EC-
specific LATS1het/LATS2homo-EKO hypercholesteremic (H-chol) mice; we detected a plaque erosion-like lesions
at h- and d-flow areas in the aortic arch and carotids, which revealed strong fibrin/fibrinogen positive organized
thrombus formation without a large necrotic core. We observed significant increases in 1) EC proliferation, 2)
EC apoptosis with senescent phenotype, 3) tissue factor (TF) expression, and 4) inflammation, which are
collectively referred to as the “pro-thrombotic phenotype”. We hypothesize that pathological flow-induced
LATS1/2 degradation promotes EC damage-mediated thrombus formation and luminal re-endothelialization in
concert. This cycle of EC damage-thrombus-re-endothelialization results in largethrombus formation and
plaque erosion. Pathological flow-induced MAGI1 S741 phosphorylation by PKC, and the subsequent
LATS1/2-TERF2IP-MKRN1 complex formation are essential for LATS1/2 degradation. To test ths hypothesis,
we propose the following 3 aims. In aim 1, we will characterize the role of excess EC proliferation,
senescence/apoptosis, tissue factor (TF) expression, and inflammation in the formation of plaque erosion-like
lesions and intraplaque hemorrhage in EC specific Lats1het/Lats2homo knock-out (Lats1het/Lats2homo-EKO) mice
under H-chol. In aim 2, we will determine the crucial role of phosphorylation dependent TERF2IP and MKRN1
Ub E3 ligase binding in pathological flow-induced LATS1/2 destabilization and the consequent pro-thrombotic
phenotype, and in aim 3 we will Investigate the role of PKC-induced MAGI1 S741 phosphorylation in
LATS1/2-mediated TERF2IP S205 phosphorylation and LATS1/2 degradation. The proposed work is expected
to establish the link between pathological flow and pro-thrombotic phenotype, by which high-risk plaques are
formed. The proposed study is innovative because it will propose a new concept how pathological flow affects
the endothelium and induce the formation of vulnerable plaques of erosion and will provide insights into new
signaling cascades and molecules responsible for this pathology. The proposed research may also provide
means to predict and ...

## Key facts

- **NIH application ID:** 9974575
- **Project number:** 5R01HL149303-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jun-Ichi Abe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $793,939
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974575

## Citation

> US National Institutes of Health, RePORTER application 9974575, Pathological flow-induced endothelial damage and plaque erosion (5R01HL149303-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974575. Licensed CC0.

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