# The Role of the Thrombospondins in Intimal Hyperplasia

> **NIH NIH R01** · LOYOLA UNIVERSITY CHICAGO · 2020 · $382,291

## Abstract

Restenosis secondary to intimal hyperplasia (IH) after balloon angioplasty to treat arterial blockages in
peripheral arteries is a significant cause of disability and death. The thrombospondins (TSPs) are
multifunctional matricellular proteins central to the development of intimal hyperplasia. They are not part of the
arterial wall structure, but exert their physiologic effects on arterial structure by binding cytokines, cell-surface
receptors, proteases and other proteins. This proposal focuses on three TSPs integral to the development of
intimal hyperplasia – TSP-1, TSP-2 and TSP-5. We have studied the effects of TSP-1 on vascular smooth
muscle cell (VSMC) proliferation and migration and its importance in the development of intimal hyperplasia;
however, increasing evidence exists that TSP-2 and TSP-5 have separate and contributory roles in this
pathology. All three TSPs are substrates of ADAMTS (A Disintegrin And Metalloproteinase with
Thrombospondin Motifs) proteins. ADAMTSs digest TSPs, enhancing or inhibiting TSP function, since the
fragments left after digestion have distinct effects themselves on intimal hyperplasia. Therefore, ADAMTS-1,-4,
and-7 will also be studied as they are involved in PAD and were also identified to be regulated by TSPs in our
prior VSMC gene study. Our long-term goal is to understand how TSPs can be manipulated therapeutically to
prevent intimal hyperplasia in vivo. The objective of this proposal is to determine how TSP-1, TSP-2 and TSP-5
specifically contribute to the development of intimal hyperplasia. Our central hypothesis is that the expression,
bioavailability, signaling pathways and changes in gene expression induced by TSP-1, TSP-2 and TSP-5 and
their interactions with ADAMTSs have distinct effects on regulating the development of IH. This hypothesis
was formulated on the basis of our strong preliminary data, our publications and the literature. The rationale for
the proposed project is that understanding the roles of TSPs on intimal hyperplasia will result in identification of
therapeutic targets to inhibit intimal hyperplasia and restenosis after balloon angioplasty. Our hypothesis will be
tested by pursuing the following Specific Aims: 1) determine the role that TSP-1, TSP-2 and TSP-5 each have
on intimal hyperplasia; 2) determine the differential effects of TSP-1, TSP-2 and TSP-5 on protein and
microRNA expression (i.e., miR-17~92 cluster), and their downstream effects on VSMC function; and 3)
establish the role of ADAMTSs in TSP-1, TSP-2 and TSP-5 activity and in the development of intimal
hyperplasia. The methodologies utilized to investigate these Specific Aims include: 1) modified Boyden
chamber to assess chemotaxis and colorimetric assay to assess for proliferation in VSMCs; 2) western blot,
ELISA and immunoPCR for cell signaling and protein expression; 3) quantitative real time polymerase chain
reaction for gene expression; 4) two animal models of intimal hyperplasia – common carotid artery balloon...

## Key facts

- **NIH application ID:** 10044162
- **Project number:** 7R01HL133577-04
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Vivian Gahtan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,291
- **Award type:** 7
- **Project period:** 2019-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044162

## Citation

> US National Institutes of Health, RePORTER application 10044162, The Role of the Thrombospondins in Intimal Hyperplasia (7R01HL133577-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10044162. Licensed CC0.

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