# Vascular Pathogenesis of Port Wine Stain

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $308,874

## Abstract

PROJECT SUMMARY
Port Wine Stain (PWS) is a congenital, progressive vascular malformation of human skin which occurs in an
estimated incidence of 3-5 infants per 1,000 live births. Approximately 1.2 million individuals in the United
States have PWS birthmarks. Pulsed dye laser (PDL) remains the choice of treatment for PWS. However, only
less than 10% of patients achieve complete lesion fading after PDL. Inadequate PWS therapeutic outcome is a
clinically significant problem that requires an urgent solution. The etiology and pathogenesis of PWS are
currently poorly understood. This knowledge gap is a major obstacle for developing any new effective
treatments. PWS is one of the research areas under the NIAMS long-range plan listed as “understanding the
cause of skin vasculature birth defects (e.g., hemangioma and port wine stain) and developing effective
therapies.” The studies proposed herein are specifically directed towards understanding pathological
mechanisms of PWS and facilitating the development of new, more effective approaches to treatment. In
searching for causative substances for PWS, we have identified that circulating CD31+ exosomes, which are
derived from human lesional dermal microvascular endothelial cells (hDMVECs), facilitate the formation of
vascular phenotypes of PWS. Analysis of the protein content of the serum CD31+ exosomes reveals that PWS
CD31+ exosomes harbor a unique molecular milieu that include EphB1, ephrinB2 (EfnB2), a-disintegrin-and-
metalloprotease domain 30 (ADAM30), and exocytosis mediator synatotagamin like-1 (SYTL1). Functional
analysis shows ADAM30 functions as a sheddase to cleave EfnB2 and its activity is regulated by vascular
endothelial growth factor receptor 2 (VEGFR2) signaling. More interestingly, compared to normal controls,
PWS serum CD31+ exosomes and hDMVEC culture-derived EphB1/EfnB2/ADAM30 exosomes possess much
greater angiogenesis activity. They greatly increased the number and size of new blood vessels formed in a
nude mouse xenograft model in vivo. These novel findings motivate us to test a hypothesis that hDMVEC-
derived CD31+ exosomes enrich at lesional sites and cause the development and progression of PWS via
disruption of cell-cell and cell-ECM interactions and EC barrier function through a molecular pathway
involving exosomal EphB1/EfnB2/ADAM30 (Fig. 1). These exosomes are also released into the circulatory
system where they can be identified and serve as potential serum biomarkers. In Aim 1, we will determine
the specific molecular profiles of CD31+ exosomes derived from PWS ECs as compared to normal controls in
vitro and in vivo. We will determine if secretion of CD31+ exosomes from PWS hDMVECs is regulated by
exocytosis genes SYTL1 and synatotagamin-1 (SYT1) in vivo and in vitro; In Aim 2, we will determine the
mechanisms by which EphB1/EfnB2 regulates VEGFR2 signaling to activate ADAM30 leading to subsequent
EfnB2 cleavage; in Aim 3, we will determine if PWS CD31+ exosomal EphB1/EfnB2/...

## Key facts

- **NIH application ID:** 9917754
- **Project number:** 5R01AR073172-04
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Wenbin Tan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,874
- **Award type:** 5
- **Project period:** 2019-01-08 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917754

## Citation

> US National Institutes of Health, RePORTER application 9917754, Vascular Pathogenesis of Port Wine Stain (5R01AR073172-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9917754. Licensed CC0.

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