# Mechanosensing and Mechanotransduction in the Endothelial Nucleus

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2024 · $44,262

## Abstract

Project Summary/Abstract
Vascular cells are constantly subjected to physical forces associated with the rhythmic activities of the heart,
which combined with the individual geometry of vessels further imposes oscillatory, disturbed, or laminar shear
stresses on endothelial cells. These hemodynamic forces dictate the phenotype and gene expression profile of
endothelial cells in different regions of the arterial tree making them athero-protective or athero-prone. Due to
the impact of distinct types of flow in the onset of vascular pathology, significant effort has been placed in
identifying mechanosensing proteins and transcriptional profiles linked to different types of shear stress. In
contrast, less emphasis has been given to how forces at the cell surface are transmitted to the nucleus,
impacting nuclear shape, nuclear pore function, and chromatin organization and integrity in the vasculature,
which is the focus of this application. I found that oscillatory and disturbed flow have a progressive deleterious
effect in nuclear shape, which is exacerbated by loss of vimentin. Based on this and other preliminary data, I
hypothesize that Vimentin is critical for maintaining nuclear shape and chromatin integrity in regions of oscillatory
and disturbed flow in the endothelium. Using endothelial cells in vitro for mechanistic studies and vimentin null
mice for in vivo validation, I will complete an in-depth characterization of changes in nuclear integrity and function
in dysmorphic nuclei associated with aging and loss of vimentin. I will begin with a detailed characterization of
nuclear shape, nuclear membrane integrity, and function (via analysis of nuclear-cytoplasmic transport) in ECs
under non-laminar flow both in vivo, in the aortic endothelium, and in vitro using live-cell imaging, and atomic
force microscopy. I also will characterize vimentin kinetics, including its post-translational modifications, under
non-laminar flow (Aim 1). To assess shifts in transcriptional and signaling networks, I will use scRNA sequencing
and proteomics to identify and validate the vimentin interactome. I will examine the consequence of vimentin
loss on proteins of the Linker of Nucleoskeleton to Cytoskeleton (LINC) complex which directly or indirectly
interact with vimentin and are involved in direct force transmission to the nucleus (Aim 2). Finally, I will evaluate
how loss of vimentin alters endothelial chromatin integrity and epigenetic states using ATAC-sequencing to
provide evidence of vimentin’s critical function in maintaining chromatin homeostasis in the vasculature (Aim 3).
Through the completion of this proposed work, I will significantly expand my toolkit of techniques, skills, and
concepts while actively contributing to clarify the impact of physical forces on the endothelial nucleus. I am also
looking forward to broadening my skills in working with large datasets including analysis, distillation of information
and deriving new questions. As part of thi...

## Key facts

- **NIH application ID:** 10893581
- **Project number:** 5F31HL165767-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jocelynda Salvador
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,262
- **Award type:** 5
- **Project period:** 2022-09-08 → 2025-09-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893581

## Citation

> US National Institutes of Health, RePORTER application 10893581, Mechanosensing and Mechanotransduction in the Endothelial Nucleus (5F31HL165767-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10893581. Licensed CC0.

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