MDC Lab Coats

Blood vessel function and target-organ damage

Blood vessel function and target-organ damage

Our group focuses on ion channels, primarily in vascular smooth muscle cells (VSMC), to clarify mechanisms contributing to hypertension and cardiovascular disease. Potassium channels, chloride channels and transient receptor potential (TRP) channels have received special attention. In collaboration with Björn Schroeder, we investigated the role of smooth muscle TMEM16a chloride channels. We showed that VSMC TMEM16 channels function as regulator of agonist-dependent arterial constriction and systemic blood pressure. In collaboration with Thomas Jentsch and Michael Bader, we provided definitive evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand-independent, mechanoactivation of AT1R subtype a. We are currently studying biased agonism and ryanodine receptor isoforms (Figure 1) in VSMC potassium channels gating and myogenic tone.  A particular attention is paid to various KCNQ potassium channel isoforms in periadventitial vasoregulation.  Thomas Jentsch is helping us here. We also have a project focusing on the perivascular adipose tissue (PVAT) as a source for relaxing factors. Here, we collaborate with Wolf-Hagen Schunck, who has peaked our interests in eicosanoids. We also collaborate with Huang Yu, Hong Kong, China.  Together, we developed the novel concept that perivascular adipose tissue (PVAT) function requires considering heterogeneous PVAT as a specialized organ that can differentially regulate vascular function depending on its anatomical location.   Finally, in collaboration with the German Institute of Human Nutrition (DifE), we are studying human diabetic nephropathy with a focus on genetics.

Figure 1. Intracellular release of calcium ions by ryanodine type II receptor calcium channels in mesenteric artery smooth muscle cells.
Intracellular calcium release is visualized by calcium sensitive dyes and Nipkow spinning disc microscopy. Three freshly-isolated cells are shown in this figure: The upper two cells are isolated from wild-type (WT) mice; the lower cell is isolated from a ryanodine receptor type 2 deficient (KO) mouse. The stimulator of intracellular ryanodine receptors caffeine (10 mM) induced a strong calcium release signal in WT, but not in KO cells

TMEM16a and TRP channels

TMEM16a, TRPC6, and TRPV1 channels are expressed in the vasculature. We used smooth muscle specific TMEM16a deficient mice and found that TMEM16a downregulates agonist-induced vasoconstrictions and thereby contributes to blood pressure regulation. Our current research in this area is directed towards identifying role of TMEM16a and ryanodine receptor isoforms in collateral arterial networks. In collaboration with Ferdinand Le Noble, we have examined the role of the Notch ligand Delta-like 4 (Dll4) in formation of collateral arterial networks and in peripheral ischemia. We found that loss of Dll4 in mice stimulates collateral formation and angiogenesis, but in ischemia such beneficial effects are overruled by adverse vessel functionality. We have also examined TRPV1 and TRPV4 channels in regulating renal blood flow. We found that TRPV1 channels can contribute to ischemia/reperfusion (I/R) -induced kidney injury.

Eicosanoids, H2S and inflammation

EETs serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect cardiovascular function by anti-inflammatory mechanisms. Our current research in this area is directed towards identifying the role of H2S producing enzymes as regulator of vasodilatory EETs and nitric oxide (NO).  In diabetes mellitus, insulin-induced relaxation of arteries is impaired and the level of ortho-tyrosine (o-Tyr), an oxidized amino acid is increased.  We found that elevated levels of o-Tyr contribute to vasomotor dysfunction in diabetes mellitus. We also identified a novel role of Anti-AT1 receptor and –ETA receptor antibodies in pulmonary arterial hypertension associated with systemic sclerosis. Both antibodies may contribute to pulmonary hypertension via increased vascular endothelial reactivity and induction of pulmonary vasculopathy. In collaboration with Ralf Dechend, we also identified a novel role of vitamin D in hypertension and target-organ damage. Our data suggest that even short-term severe vitamin D deficiency may directly promote hypertension and impacts on renin-angiotensin system components that could contribute to target-organ damage.

Vasodilator signals from perivascular adipose tissue

We have identified a vasorelaxing factor produced in the perivascular adipose tissue (ADRF). Our recent work showed that KCNQ channels could represent the subtype of Kv channels involved. The "third gas", namely H2S, could represent ADRF. However, other adipokines may also play a role. We identified alterations in the paracrine control of arterial tone by periadventitial adipose tissue in animal models of hypertension and metabolic disease. KCNQ and cystathionine gamma-lyase deficient mice are available to us to clarify the role of Kv channels and H2S. ADRF and its putative targets (KCNQ channels) might represent exciting new targets for the development of drugs for treatment of cardiovascular and metabolic disorders.

Genetic renal diseases

An outgrowth of Maik Gollasch’s clinical responsibilities has been a focus on clinical genetics related to renal diseases. We have performed functional analyses of mutations causing familiar kidney diseases with specific emphasis on TRPC6 channels in focal and segmental glomerulosclerosis (FSGS). We identified a unique CD2AP mutation in a German family, supporting the overall concept that CD2AP-associated nephropathy is an autosomal dominant form of FSGS in man.  We are also studying human diabetic nephropathy with a focus on genetics. For these purposes, we recently established an Outpatient Kidney Clinic at Charité Campus Buch and the Registry of Diabetic Nephropathy ( We are continuously recruiting patients for our Registry and renal/vascular disease-specific family studies. Through these studies, we hope to identify novel mechanisms leading to increased cardiovascular risk and target-organ damage and novel treatment targets.

Primary funding

The Deutsche Forschungsgemeinschaft (GO 766/13-1, GO766/15-1; GO766/17-1; GO766/18-1, FOR1368), DAAD, Alexander von Humboldt Stiftung, ERA-EDTA and cooperative grants between the MDC and ECRC have funded this work.