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Vascular Remodelling

Projektleiter: PD Dr. rer. nat. Jennifer S. Esser

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 BMP signaling pathway

Figure 1: Activation of the signaling pathway starts with binding of dimeric ligands to type II receptors (BMPRII) which in turn recruits type I receptors (BMPRI) to build a heterodimeric receptor complex. Complex formation of the phosphorylated receptor-regulated Smads with Smad4 causes nuclear accumulation of active Smad complexes, which directly regulate gene transcription in conjunction with transcription factors. Besides this canonical Smad signaling pathway other Smad-independent alternative signaling cascades such as MAPK/Erk and PI3K/Akt pathways are activated to increase cell migration and proliferation. BMP ligands are regulated in the extracellular space by BMP antagonists (chordin, noggin) and modulators such as BMPER and twisted gastrulation (Tsg).

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).

PD Dr. rer. nat. Jennifer S. Esser

PD Dr. rer. nat. Jennifer S. Esser (née Heinke)
Group leader, PI

Tel.: +49-761-270-70440
Fax: +49-761-270-70450
Email: jennifer.esser@uniklinik-freiburg.de

Bianca Engert
Technician

Email: bianca.engert@uniklinik-freiburg.de

Roman Gösele

Roman Gösele
Medical Student

Email: Roman.Goesele@universitaets-herzzentrum.de

Kora Prölß

Kora Prölß
Medical Student

Email: Kora.Proelss@universitaets-herzzentrum.de

Lena Meier

Lena Meier
Veterinarian

Email: Lena.Meier@universitäts-herzzentrum.de

Sophie Gläser

Sophie Gläser
Medical Student

Email: sophie.glaeser@uniklinik-freiburg.de

Jeanina Begelspacher

Jeanina Begelspacher
Veterinarian

Email: jeanina.begelspacher@uniklinik-freiburg.de

Alumni
Katia Marenne, Dr. med. vet.

Katia Marenne, Dr. med. vet.
Veterinarian

Ann-Kathrin Baur, Dr. med. dent.

Ann-Kathrin Baur, Dr. med. dent.
Dentist

Immunocytochemistry human umbilical venous endothelial cells (HUVECs)

Spheroid

Immunohistochemistry M.quadriceps; SMA staining in green (arterial blood vessel) and BMPER staining in red.

Standard molecular biology methods

  • e.g. Realtime PCR
  • Western blot
  • Cloning

Primary cell isolation and culture

  • Endothelial cells
  • Smooth muscle cells
  • Cell lines
  • Transfection of Plasmids, siRNAs, microRNAs 

Functional cell culture assays

  • Cell proliferation
  • Cell migration
  • Collagen gel contraction

Angiogenesis Assays

  • Matrigel assay
  • 3D collagen spheroid sprouting assay; mosaic spheroids
  • Aortic ring assay
  • Matrigel plug assay 

In vivo models for

  • Angiogenesis
  • Aortic aneurysm
  • Carotis Restenosis
  • PAD

Immunohistochemistry

  • Blood vessel markers, vSMC markers, ECM molecules
  • Proximity Ligation assay (PLA-Assay)
  • Zymography

2019

Reichert S, Scheid S, Roth T, Herkel M, Petrova D, Linden A, Weberbauer M, Esser J, Diehl P, Grundmann S, Busch HJ, Fink K, Bode C, Moser M, Helbing T.
Semaphorin 3F Promotes Transendothelial Migration of Leukocytes in the Inflammatory Response After Survived Cardiac Arrest.
Inflammation. 2019/Ma 15. [Epub ahead of print] PMID: 30877507 [Pubmed]

2018

Lother A, Deng L, Huck M, Fürst D, Kowalski J, Esser JS, Moser M, Bode C, Hein L.
Endothelial cell mineralocorticoid receptors oppose VEGF-induced gene expression and angiogenesis.
J Endocrinol. 2018/Sep 1. PMID: 30400069 [Epub ahead of print] (IF: 4.012) [Pubmed]

Esser JS, Steiner RE, Deckler M,Schmitt H, Engert B, Link S, Charlet A,Patterson C,Bode C, Zhou Q, Moser M.
Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells.
FEBS J. 2018/285:1419-1436. PMID: 29473997 (IF: 4.530) [Pubmed]

2017

Helbing T, Arnold L, Wiltgen G, Hirschbihl E, Gabelmann V, Hornstein A, Esser JS, Diehl P, Grundmann S, Busch HJ, Fink K, Bode C, Moser M.
Endothelial BMP4 Regulates Leukocyte Diapedesis and Promotes Inflammation.
Inflammation. 2017/40:1862-1874. PMID: 28755278 [Pubmed]

Esser JS, Saretzki E, Pankratz F, Engert B, Grundmann S, Bode C, Moser M, Zhou Q.
Bone morphogenetic protein 4 regulates micrornas mir-494 and mir-126-5p in control of endothelial cell function in angiogenesis.
Thrombosis and haemostasis. 2017. [Pubmed]

Helbing T, Wiltgen G, Hornstein A, Brauers EZ, Arnold L, Bauer A, Esser JS, Diehl P, Grundmann S, Fink K, Patterson C, Bode C, Moser M.
Bone morphogenetic protein-modulator bmper regulates endothelial barrier function.
Inflammation. 2017. http://dx.doi.org/10.1007/s10753-016-0490-4 [Pubmed]

Esser JS, Charlet A, Schmidt M, Heck S, Allen A, Lother A, Epting D, Patterson C, Bode C, Moser M.
The neuronal transcription factor npas4 is a strong inducer of sprouting angiogenesis and tip cell formation.
Cardiovasc Res. 2017;113:222-223.  [Pubmed]

2016

Rilinger J, Meyer M, Schnabel K,Weik P,Charlet A, Esser JS,Zhou Q, Bode C, Moser M,Diehl P, Olivier CB. High platelet reactivity after p2y12-inhibition in patients with atrial fibrillation and coronary stenting.
Journal of thrombosis and thrombolysis. 2016;42:558-565. [Pubmed]

Petrera A, Gassenhuber J, Ruf S, Gunasekaran D, Esser J, Shahinian JH, Hubschle T, Rutten H, Sadowski T, Schilling O.
Cathepsin a inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels.
J Transl Med. 2016;14:153. [Pubmed]

2015

Zhou Q, Gensch C, Keller C, Schmitt H, Esser J, Moser M, Liao JK.
Mntbap stimulates angiogenic functions in endothelial cells through mitofusin-1.
Vascular pharmacology. 2015;72:163-171. [Pubmed]

Pankratz F, Bemtgen X, Zeiser R, Leonhardt F, Kreuzaler S, Hilgendorf I, Smolka C, Helbing T, Hoefer I, Esser JS, Kustermann M, Moser M, Bode C, Grundmann S.
Response to letter regarding article, "microrna-155 exerts cell-specific antiangiogenic but proarteriogenic effects during adaptive neovascularization".
Circulation. 2015;132:e376. [Pubmed]

Pankratz F, Bemtgen X, Zeiser R, Leonhardt F, Kreuzaler S, Hilgendorf I, Smolka C, Helbing T, Hoefer I, Esser JS, Kustermann M, Moser M, Bode C, Grundmann S.
Microrna-155 exerts cell-specific antiangiogenic but proarteriogenic effects during adaptive neovascularization.
Circulation. 2015;131:1575-1589. [Pubmed]

Esser JS, Rahner S, Deckler M, Bode C, Patterson C, Moser M.
Fibroblast growth factor signaling pathway in endothelial cells is activated by bmper to promote angiogenesis.
Arterioscler Thromb Vasc Biol. 2015;35:358-367. [Pubmed]

2014

Hellbach N, Weise SC, Vezzali R, Wahane SD, Heidrich S, Roidl D, Pruszak J, Esser JS, Vogel T.
Neural deletion of tgfbr2 impairs angiogenesis through an altered secretome.
Hum Mol Genet. 2014;23:6177-6190. [Pubmed]

Fessner A, Esser JS, Bluhm F, Grundmann S, Zhou Q, Patterson C, Bode C, Moser M.
The transcription factor hoxb5 stimulates vascular remodelling in a cytokine-dependent manner.
Cardiovasc Res. 2014;101:247-255.  [Pubmed]

2013

Helbing T, Herold EM, Hornstein A, Wintrich S, Heinke J, Grundmann S, Patterson C, Bode C, Moser M. Inhibition of bmp activity protects epithelial barrier function in lung injury.
J Pathol. 2013;231:105-116.  [Pubmed]

Heinke J, Juschkat M, Charlet A, Mnich L, Helbing T, Bode C, Patterson C, Moser M.
Antagonism and synergy between extracellular bmp modulators tsg and bmper balance blood vessel formation.
J Cell Sci. 2013;126:3082-3094.  [Pubmed]

2012

Heinke J, Patterson C, Moser M.
Life is a pattern: Vascular assembly within the embryo.
Frontiers in bioscience (Elite edition). 2012; 4:2269-2288. [Pubmed]

Heinke J, Kerber M, Rahner S, Mnich L, Lassmann S,Helbing T, Werner M, Patterson C, Bode C, Moser M. Bone morphogenetic protein modulator bmper is highly expressed in malignant tumors and controls invasive cell behavior.
Oncogene. 2012;31:2919-2930.  [Pubmed]

2011

Helbing T, Rothweiler R, Ketterer E, Goetz L, Heinke J, Grundmann S, Duerschmied D, Patterson C, Bode C, Moser M.
Bmp activity controlled by bmper regulates the proinflammatory phenotype of endothelium.
Blood. 2011;118:5040-5049. •10.1182/blood-2011-03-339762. [Pubmed]

Grundmann S, Hans FP, Kinniry S, Heinke J, Helbing T, Bluhm F, Sluijter JP, Hoefer I, Pasterkamp G, Bode C, Moser M.
Microrna-100 regulates neovascularization by suppression of mammalian target of rapamycin in endothelial and vascular smooth muscle cells.
Circulation. 2011;123:999-1009. [Pubmed]

2010

Helbing T, Volkmar F, Goebel U, Heinke J, Diehl P, Pahl HL, Bode C, Patterson C, Moser M.
Krüppel-like factor 15 regulates bmper in endothelial cells.
Cardiovasc Res. 2010;85:551-559. [Pubmed]

Helbing T, Rothweiler R, Heinke J, Goetz L, Diehl P, Zirlik A, Patterson C, Bode C, Moser M.
Bmper is upregulated by statins and modulates endothelial inflammation by intercellular adhesion molecule-1.
Arterioscler Thromb Vasc Biol. 2010;30:554-560. •10.1161/ATVBAHA.109.201087.  [Pubmed]

2009

Winnik S, Klinkert M, Kurz H, Zoeller C, Heinke J, Wu Y, Bode C, Patterson C, Moser M.
Hoxb5 induces endothelial sprouting in vitro and modifies intussusceptive angiogenesis in vivo involving angiopoietin-2.
Cardiovasc Res. 2009;83:558-565. [Pubmed]

2008

Heinke J, Wehofsits L, Zhou Q, Zoeller C, Baar KM, Helbing T, Laib A, Augustin H, Bode C, Patterson C, Moser M.
Bmper is an endothelial cell regulator and controls bone morphogenetic protein-4-dependent angiogenesis.
Circ Res. 2008. [Pubmed]

Gruh I, Wunderlich S, Winkler M, Schwanke K, Heinke J, Blomer U, Ruhparwar A, Rohde B, Li RK, Haverich A, Martin U.
Human cmv immediate-early enhancer: A useful tool to enhance cell-type-specific expression from lentiviral vectors.
The journal of gene medicine. 2008;10:21-32.  [Pubmed]

2007

Zhou Q, Heinke J, Vargas A, Winnik S, Krauss T, Bode C, Patterson C, Moser M.
Erk signaling is a central regulator for bmp-4 dependent capillary sprouting.
Cardiovasc Res. 2007;76:390-399.  [Pubmed]


PD Dr. rer. nat. Jennifer S. Esser

PD Dr. rer. nat. Jennifer S. Esser (née Heinke)
Group leader, PI

Tel.: +49-761-270-70440
Fax: +49-761-270-70450
Email: jennifer.esser@uniklinik-freiburg.de

Project funding