# Microenvironmental Control of Capillary Morphogenesis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $570,046

## Abstract

Vascularization is of critical importance to the treatment of numerous pathologies and the
success of tissue engineering. Many cell-based strategies to promote therapeutic
vascularization have been explored in both pre-clinical models and clinical trials. However,
approaches involving delivery of a single cell type to ischemic sites either by intravenous or
intramuscular injection have shown little efficacy in clinical trials, particularly for the treatment of
critical limb ischemia. By contrast, a common approach to vascularize engineered tissues
involves co-encapsulation of endothelial cells (or their progenitors) combined with supportive
stromal cells in a hydrogel-based biomaterial intended to mimic the extracellular matrix (ECM).
However, the choices of stromal cells and materials have varied widely across studies. Our
long-term goal is to mechanistically understand how these elements of the microenvironment
influence the quantity, functional quality, and stability of the resulting vasculature. Using a
combination of in vitro and in vivo models, we have shown the rate of formation of nascent
vasculature is regulated by both the biophysical properties of the ECM and the identity of the
supporting stromal cells. Furthermore, we have demonstrated that stromal cell identity critically
regulates the functional qualities of the microvasculature formed within fibrin hydrogels, both in
vitro and in vivo, with multipotent bone marrow stromal cells (BMSCs) inducing more stable,
less permeable capillaries compared to fibroblasts from a range of different tissues. Our data
suggest stromal cells of different origins differentially remodel and stiffen the ECM to influence
the rate of vascular morphogenesis, leading to our hypothesis that vessels which form quickly
are of poor quality, while those which form more slowly show superior functionality, maturation,
and persistence. In Aim 1, a combination of approaches will be used in 3D fibrin-based co-
culture models to evaluate the impact of stromal cell identity on vascular morphogenesis rate,
ECM mechanics (global and local), and permeability. In Aim 2, an engineered hydrogel material
will be used to alter the relationships between stromal cell identity, ECM mechanics,
vascularization rate, and vascular permeability. Finally, Aim 3 will examine the effects of
stromal cell identity and morphogenesis rates on the quantity and quality of neovasculature in
multiple in vivo models. Successful completion of these aims will expand the mechanistic
insights attained during the prior funding periods to better understand the roles of the
microenvironment in vascular morphogenesis, and thereby enhance efforts to create functional
vasculature suitable for regenerative medicine and revascularization applications.

## Key facts

- **NIH application ID:** 10235621
- **Project number:** 2R01HL085339-10A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Andrew J Putnam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,046
- **Award type:** 2
- **Project period:** 2007-07-20 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235621

## Citation

> US National Institutes of Health, RePORTER application 10235621, Microenvironmental Control of Capillary Morphogenesis (2R01HL085339-10A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10235621. Licensed CC0.

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