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AG Vascular Remodelling


Overview

Research Group „Vascular Remodelling" (Jennifer S. Esser, PhD)

The main research focus of our group is in the field of vascular biology and vascular disease. Specifically, we aim to identify the role of the BMP pathway in vascular cells (vascular smooth muscle cells [vSMCs] and endothelial cells) and in cardiovascular diseases such as peripheral artery disease, restenosis, hypertension and aneurysm. The importance of an entirely matured and healthy vasculature becomes evident during embryonic development because mice failing to establish functional blood vessels die around day 10. Accordingly, malformations or dysfunction of the vascular system have a huge impact on the whole organism and lead to pathogenesis of many diseases. For instance ischemic vascular disease such as coronary heart disease (CHD) and peripheral artery disease (PAD), degenerative vascular diseases such as aortic aneurysm and pathological neovascularization such as tumor angiogenesis.

Neovascularization

Angiogenesis is defined as the growth of new blood vessels from pre-existing vessels, whereas vasculogenesis is the process of de novo differentiation of endothelial cells from mesodermal precursor cells. Sprouting angiogenesis is often activated by hypoxia and is invasive to unvascularized tissues, but the process is relatively slow and depends on cell proliferation. In order to achieve a functional blood vessel endothelial cell behavior such as migration, proliferation and sprout formation has to be fine-tuned by interacting pro- and antiangiogenic signals For example, the well-known vascular endothelial growth factor (VEGF) activates multiple intracellular signaling cascades by binding to its receptor VEGFR2, subsequently facilitating endothelial cell sprouting and survival. As a third mechanism in neovascularization arteriogenesis is defined as growth of functional collateral arteries from preexisting arterio-arteriolar anastomoses that finally leads to luminal augmentation of pre-existing vessels. Besides endothelial cells, vSMCs)are mainly responsible for the enlargement of vascular wall structures. Reperfusion of ischemic tissue, as for instance in CHD, needs to be improved that can be achieved by therapeutic angiogenesis and application of pro-angiogenic substances. Due to its high clinical relevance the characterization of new molecule and signalling pathways that drive the molecular and cellular mechanisms in neovascularization is the central research topic of this group. Here, the focus is particularly on members of the bone morphogenetic protein (BMP) signaling pathway.

Bone morphogenetic proteins (BMPs)

Bone morphogenetic proteins (BMPs) are extracellular growth factors that are produced by multiple cell types and participate in a wide array of cellular responses, such as proliferation, angiogenesis, differentiation and apoptosis. BMPs signal through cell surface complexes of type I (Alk3/BMPR1a and Alk6/BMPR1B) and type II (BMPRII) serine/threonine kinase receptors. Upon activation, the receptors mediate intracellular signalling via Smad 1/5 transcription factors targeting Id1 transcription factor, which is a well-known BMP target gene. In the extracellular space the availability of BMPs is regulated by BMP antagonists such as Chordin, Noggin, and BMP modulators such as BMP endothelial cell precursor derived regulator (BMPER).

The components of the BMP signaling pathway, ligands, receptors and intracellular signaling molecules, are all expressed in vascular cells. In line with a key role for BMPs in vascular development loss of function models of BMP ligands, the BMP receptors, or Smad 1/5 show early embryonic lethality due to disturbed mesoderm development and thus reduced vasculature. Like endothelial cells, vSMCs play an important role for the physiological function of arterial blood vessels and are known to lose their contractile phenotype in vascular diseases such as atherosclerosis. This results in a shift of vSMCs into a dedifferentiated synthetic phenotype that is characterized by increased cell proliferation and vSMCs migration. The transforming growth factor-β (TGF-β) and the BMPs have been implicated as important regulators of vSMCs plasticity. Therefore, we aim to understand how members of the BMP pathway, and especially, BMPER regulates the vSMC phenotype. By combining up to date molecular- and cell biology techniques with a wide range of experimental models, the Vascular Remodelling group is well embedded in the local research community,works in close collaboration within the UHZ and, especially, the Department of Cardiology & Angiology I (especially with research groups Zhou, Moser, Helbing and Grundmann).

Project funding:

Contact

Dr.rer.nat J. S. Esser
(née Heinke)
Projektleiterin
Principal Investigator

Tel: +49-761-270-70440
e-mail: Jennifer.Esser @universitaets-herzzentrum.de