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Research Group Frye
Vascular Biology
Aim
Our lab studies how endothelial cells are regulated and communicate via their extracellular microenvironment to coordinate vascular development and organ function.
Scope of Research
(Lymph)angiogenesis • Endothelial cell junctions • Extracellular matrix and tissue stiffness • Angiocrine signaling
Research Projects
1. PDE2A in the developing heart
Phosphodiesterase 2A (PDE2A) modulates cGMP and cAMP levels in several cell types. We found that deletion of endothelial Pde2a in the developing heart leads to severe cardiac defects, including ventricular septal defects, non-compaction, and hypertrabeculation. Using single-cell RNA sequencing, Xenium spatial transcriptomics, whole-heart 3D imaging, and endothelial/cardiomyocyte co-culture systems, we are investigating how angiocrine signaling influences cardiomyocyte development. Our goal is to unravel the PDE2A-driven mechanisms by which cardiac endothelial cells (CECs) instruct cardiomyocyte (CM) organization and maturation during cardiac morphogenesis.
2. Mechanoregulation via changes of substrate stiffness
This project investigates how endothelial cells (ECs), including lymphatic (LECs) and blood vascular (BECs) subtypes, as well as CMs sense and respond to changes in tissue stiffness - a crucial but incompletely understood factor in (cardio)vascular biology. We are currently mapping in vivo stiffness across developmental stages and organs, engineering hydrogels that mimic diverse tissue environments, analyzing stiffness-dependent gene expression in cultured ECs and CMs, and developing optical stiffness sensors for precise mechanical measurements. Through these approaches, we aim to understand differential mechanoregulation between EC subtypes and improve (cardio)vascular experimental models.
3. Tissue stiffening in cardiovascular disease
Cardiovascular disease (CVD) is closely linked to changes in tissue stiffness, which disrupt EC function and contribute to disease progression, yet how cardiac and aortic ECs sense and respond to these mechanical cues remains poorly understood. Here, we aim to uncover how cardiac and aortic ECs adapt to mechanical changes in their environment and to identify key molecular regulators and potential biomarkers of tissue stiffness-induced endothelial dysfunction. We combine tissue stiffness mapping, molecular analyses, and genetic manipulation to advance early detection and therapeutic strategies for CVD.
4. PDE2A in the adult lymphatic vasculature
We have recently shown that PDE2A regulates cGMP levels differentially in LECs versus venous ECs (Carlantoni et al. 2024). In LECs deletion of PDE2A leads to elevated cGMP levels, increased p38 activity, and reduced Notch signaling. These changes result in severe lymphatic dysplasia and impaired maturation of lymphatic junctions during embryonic development, while venous ECs remain unaffected. We are currently investigating how PDE2A controls in particular the function of large lymphatic collectors in the postnatal and adult stages.
5. Endothelial XPR1 controls body phosphate homeostasis
Inorganic phosphate is essential for cellular metabolism and systemic functions, yet how ECs contribute to phosphate regulation remains understudied. Our project investigates the role of the phosphate exporter Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in ECs, exploring its impact on (cardio)vascular health, systemic phosphate homeostasis, and diseases such as primary familial brain calcification.
Key Techniques
- Advanced 2D/3D hydrogel stiffness cultures for human primary endothelial cells
- Endothelial cell/cardiomyocyte co-culture systems
- Constitutive and inducible endothelial-specific Cre-loxP mouse models
- Wholemount tissue and vibratome-section immunofluorescence imaging
- Ex vivo and in vivo multiphoton microscopy
- Atomic force microscopy and nanoindentation for tissue stiffness measurements
- AVV-based optical stiffness sensors
- Single-cell RNA-seq, single-nucleus ATAC-seq, bulk RNA and ATAC sequencing, and spatial transcriptomics
Group Members
Publications
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The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-dependent notch signaling.
Carlantoni et al.
Developmental Cell 2024 doi:10.1016/j.devcel.2023.12.002 -
EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis.
Zink & Frye et al.
EMBO Reports 2021 doi: 10.15252/embr.201948961. -
Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.
Englert et al.
EBioMedicine 2021 doi: 10.1016/j.ebiom.2021.103382. -
Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program.
Frye et al.
Nature Communications 2018 doi: 10.1038/s41467-018-03959-6. -
Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin.
Frye et al.
Journal of Experimental Medicine 2015 doi:10.1084/jem.20150718
Grants/Awards
- 3R Funding from the Authority for Science, Research and Equality (City of Hamburg), 2023-2027
- DFG Project Grant “New functions of phosphodiesterase 2A in the lymphatic and blood vasculature”, 2020-2027 (initial and renewal application)
- DZHK Site Project “The interplay of matrix stiffness changes and endothelial dysfunction in cardiovascular disease”, 2026-2030
- DZHK Postdoc Grant “Regulation of cardiomyocyte phosphate homeostasis and its role in cardiomyopathy” for Claudia Carlantoni, 2026-2027
Most important collaboration partners
- René Hägerling, Charité Berlin, Germany
- Friederike Cuello, UKE, Germany
- Joanna Kalucka, Aarhus University, Denmark
- Kaska Koltowska, Uppsala University, Sweden