# Vascular Smooth Muscle Lysyl Oxidase Mediated Increase in Vessel Stiffness and its Effect on Rho-Kinase Mechanosensors: A Novel Mechanism of Atherosclerosis in Chronic Kidney Disease?

> **NIH NIH K08** · UNIVERSITY OF FLORIDA · 2020 · $84,941

## Abstract

Cardiovascular disease is the leading cause of death in Chronic Kidney Disease (CKD). Arterial stiffness is
increased in CKD, correlates with mortality, and is thought to be a key mediator of adverse cardiovascular
events. However, the molecular mechanisms by which CKD causes increased arterial stiffness and how
stiffness accelerates atherosclerosis is uncertain.
Our novel preliminary data demonstrates that lysyl oxidase (LOX), an enzyme that crosslinks collagen and
elastin, is up-regulated in vascular smooth muscle cells in CKD and could contribute to increased arterial
stiffness. The increased stiffness in turn activates the rho-kinase isoform, ROCK1 which has been shown to
increase migration and proliferation of vascular smooth muscle cells. These data suggest that atherosclerosis
might be a consequence of stiffness and points to a primary, vascular smooth muscle cell dysfunction in CKD.
The specific aims of this proposal are to (1) characterize the role of lysyl oxidase in mediating arterial stiffness
in CKD, (2) define the role of ROCK1 in the regulation of smooth muscle migration and proliferation in
response to stiffness, and (3) evaluate the role of lysyl oxidase and rho kinase in atherosclerosis in a CKD
model in vivo. The successful completion of these specific aims will define the potential of targeting vessel
stiffness as a potential mechanism to prevent vascular dysfunction of CKD. Vascular smooth muscle cells
could be a new target for the prevention of cardiovascular complications in CKD patients and the basis for
developing an independent line of research for Dr. Mohandas.
Dr. Mohandas has completed a NIH sponsored T32 research fellowship, published 13 first or senior author
papers and presented at national and international scientific meetings. He was recruited as a `Tenure Track
Assistant Professor' at the University of Florida because of his outstanding track record and potential to be an
independent physician scientist. To this end, a comprehensive but focused training program has been
designed to enhance Dr. Mohandas' training in vascular physiology and molecular biology. This includes
hands-on training in animal models of kidney disease, innovative genome editing tools, pressure arteriography,
didactic coursework in cell signaling and vascular physiology, as well as seminars and journal clubs. Dr. Mark
Segal, a highly regarded physician and expert in atherosclerosis and molecular biology, will serve as the
candidate's mentor. An Advisory Committee has been assembled to aid the candidate in scientific and career
development including Dr. Kirk Conrad (vascular physiology), Dr. Peter Sayeski (cell signaling), and Dr. Carl
Pepine (experimental and clinical cardiovascular diseases).
The outstanding environment of the University of Florida, rich in clinical and basic sciences, together with the
scientific plan and comprehensive training program, will ensure the success of Dr. Mohandas as an
independent investigator in the field of ...

## Key facts

- **NIH application ID:** 9926121
- **Project number:** 5K08HL130945-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Rajesh Mohandas
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $84,941
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-01-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926121

## Citation

> US National Institutes of Health, RePORTER application 9926121, Vascular Smooth Muscle Lysyl Oxidase Mediated Increase in Vessel Stiffness and its Effect on Rho-Kinase Mechanosensors: A Novel Mechanism of Atherosclerosis in Chronic Kidney Disease? (5K08HL130945-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926121. Licensed CC0.

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