# Role of Retinal Capillary Stiffness in Diabetic Retinopathy

> **NIH NIH R01** · DOHENY EYE INSTITUTE · 2021 · $377,419

## Abstract

PROJECT ABSTRACT
 Diabetic retinopathy (DR) is a major, potentially blinding, microvascular complication of diabetes
and the leading cause of vision loss in the working-age population. Although current clinical therapies
aim to resolve the advanced stages of DR, there is a recognition that more effective DR management
can be achieved by tackling the disease at the early stage. Diabetes-induced retinal inflammation is
strongly implicated in the pathogenesis of DR. Retinal endothelial activation (ICAM-1 expression) plays
a major role in inflammation because inhibiting ICAM-1 alone blocks retinal capillary leukostasis,
hyperpermeability, and degeneration associated with DR. But precisely how retinal endothelial cells
(ECs) become activated in diabetes is not properly understood. Since diabetes has been strongly
associated with increased stiffness of the aorta and arteries, which undergo chronic inflammation, we
asked whether diabetes also leads to stiffening of retinal capillaries and, if so, whether the increased
capillary stiffness promotes retinal inflammation in diabetes. Our preliminary data has revealed that retinal
capillaries in diabetic mice are significantly stiffer than those in normal mice, which correlates with
increased lysyl oxidase (LOX) expression. Pharmacological inhibition of LOX-dependent capillary
stiffening alone blocks retinal endothelial ICAM-1 associated with diabetes. Our preliminary studies have
also revealed that this stiffness-dependent control of retinal inflammation in diabetes is mediated by the
mechanosensitive and proinflammatory small GTPase Rho and its downstream effector ROCK, which is
markedly upregulated in retinal capillaries of diabetic mice and HG-treated retinal EC cultures. Based on
these observations, we hypothesize that diabetes leads to LOX-dependent stiffening of retinal capillaries
and elevated Rho/ROCK that, in turn, promotes NF-kB-mediated endothelial ICAM-1 expression and
retinal inflammation associated with early DR. The objective of this proposal is to uncover the link
between diabetes, retinal capillary stiffness, endothelial mechanotransduction, and retinal inflammation.
To achieve this goal, we will pursue the following specific aims. Aim 1: To fully examine the effects of
pharmacologic and genetic inhibition of LOX on retinal capillary stiffening-dependent inflammation and
vascular lesions of early DR; Aim 2: To determine the extent to which diabetes-induced biochemical
changes in the retina contribute to LOX-dependent retinal capillary stiffening; and Aim 3: To delineate
the mechanotransduction mechanism underlying capillary stiffening-dependent retinal inflammation in
diabetes.

## Key facts

- **NIH application ID:** 10254367
- **Project number:** 5R01EY028242-06
- **Recipient organization:** DOHENY EYE INSTITUTE
- **Principal Investigator:** KAUSTABH GHOSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,419
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254367

## Citation

> US National Institutes of Health, RePORTER application 10254367, Role of Retinal Capillary Stiffness in Diabetic Retinopathy (5R01EY028242-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10254367. Licensed CC0.

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