# Molecular mechanisms of Foxc-mediated angiogenesis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $466,100

## Abstract

Formation of the blood vasculature depends on the precise control of molecular networks that are tightly
regulated by proangiogenic growth factors and by molecules involved in endothelial cell (EC) metabolism.
However, the transcriptional control of these processes remains incompletely understood. The long-term goal
of our lab is to elucidate the fundamental mechanisms that regulate the formation of blood vessels and to
understand how the disruption of these mechanisms leads to vascular defects in pathological settings. FOXC1
and FOXC2 are closely related members of the FOX (Forkhead box) transcription factor family and have
critical roles in vascular development and disease. Mutations or changes in the copy number of human FOXC1
are associated with autosomal-dominant Axenfeld-Rieger syndrome (ARS), which is characterized by anterior
eye segment defects and cerebral small vessel disease, while inactivating mutations of FOXC2 are responsible
for autosomal-dominant lymphedema-distichiasis syndrome, which includes symptoms such as late-onset
lymphedema and extra eyelashes (distichiasis). We have completed preliminary experiments suggesting (1)
that the mutations are associated with declines in filopodia formation and proliferation at the angiogenic front,
defects in vascular density and branching in the capillary plexus, and impaired vascular patterning; and (2) that
these angiogenic defects are accompanied by significant declines in the activity of mammalian target of
rapamycin (mTOR) and in the expression of CD98, which imports essential amino acids such as leucine while
exporting the nonessential amino acid glutamine. Thus, our central hypothesis is that the Foxc transcription
factors participate in physiological and pathological angiogenesis by regulating pathways involved in amino
acid transport, EC metabolism, and mTOR signaling. Guided by strong preliminary data, this hypothesis will be
tested by pursuing two specific aims: 1) identify the molecular and genetic networks that link the Foxc
transcription factors with angiogenesis and EC metabolism; 2) Define the mechanisms by which Foxc1 and
Foxc2 cooperatively participate in physiological and pathological angiogenesis. In summary, the results
generated from the experiments described in this proposal will provide crucial information about the formation
of blood vessels; thus, because vascular deficiencies are among the leading causes of cardiovascular disease
and disorders, our findings are likely to identify new targets and therapeutic strategies for improving vascular
formation and function in affected patients.

## Key facts

- **NIH application ID:** 9964527
- **Project number:** 5R01HL144129-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Tsutomu Kume
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,100
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964527

## Citation

> US National Institutes of Health, RePORTER application 9964527, Molecular mechanisms of Foxc-mediated angiogenesis (5R01HL144129-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964527. Licensed CC0.

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