DeutschEnglish

New signaling pathway of blood pressure regulation

Confocal imaging of a mouse descending aorta. Blue: nuclei, Green: membrane of endothelial cells, Red: transcription factor expressed by endothelial cells. The picture represents a maximum intensity projection of several optical plane images. © MPI HLR 2019

Tension and diameter of blood vessels are continuously modulated by vasodilator and vasoconstrictor substances. If the vessel is constricted, the blood pressure rises, which in the long run damages the vessels and increases the risk of cardiovascular disease, heart attack and stroke. Stefan Offermanns' research group at the Max Planck Institute for Cardiac and Lung Research was able to elucidate a previously unknown mechanism that plays an important role in blood pressure regulation. In the future, the precise knowledge of these processes could enable scientists to intervene in pathological regulatory processes and thus prevent the consequences of arterial hypertension.

 

All blood vessels, from the largest to the smallest artery, share the multi-layered structure of their vessel wall. The innermost layer, the endothelium, is in direct contact with the blood flow, and exposed to shear stress. Shear stress is an essential physical regulator of the vessel diameter and thus of the vascular resistance that the heart has to overcome. This rises the question how these mechanical signals in the endothelium are translated into biological signals. Previous studies on this question have focused on calcium-mediated signaling pathways. They indicate that protein kinase A (PKA) could also contribute to the adaptation of blood pressure through the formation of nitric oxide (NO). However, up to date it remained unclear how the regulation via PKA actually takes place.

As part of an international collaboration, a research team led by Stefan Offermanns has now identified the signal path responsible for the transmission of the shear stress signal via PKA. Its main focus lies on the vasodilator peptide adrenomedullin. This messenger substance was termed after the adrenal medulla, where it was discovered. In fact, Andromedullin can be found in numerous tissues. It plays a key role in the regulation of cardiovascular and pulmonary homoeostasis and is considered a vasoprotective factor.

"We already knew that shear stress forces lead to the release of adrenomedullin. However, the mechanism of the release was completely unclear. Our goal was to elucidate the exact mechanisms of this signaling cascade," explains Andras Iring, first author of the publication. Using isolated endothelial cells and a knockout mouse model, the researchers were able to show for the first time how the signaling actually takes place.

The signalling pathway works via the activation of the mechanosensitive cation channel PIEZO 1:  PIEZO 1 triggers the release of andromedullin. Andromedullin binds to the adrenomedullin receptor (also known as calcitonin like receptor, Calcrl) and activates protein kinase A via cAMP. Protein kinase A phosphorylates endothelial nitric oxide synthase (eNOS), a key enzyme in blood pressure regulation. As a result, the amount of the vasodilator and thus blood pressure-lowering messenger substance nitric oxide (NO) increases.

Suppression of the starting point of this signaling pathway, the PIEZO1 channel, resulted in a significant decrease in adrenomedullin levels. Furthermore, the suppression of genes coding for adrenomedullin or its receptor significantly reduced vasodilatation in response to blood flow. The result: an artificially induced arterial hypertension. Stefan Offermanns: "Our work shows how blood flow leads to vasodilatation in healthy organisms. In the future, this knowledge may contribute to the development of new treatments for diseases with impaired vascular regulation, such as high blood pressure or atherosclerosis."

 

VG/SO

 

Original publication:

 

Iring A., Jin Y., Albarrán-Juárez J., Siragusa M., Wang S., Dancs P., Nakayama A., Tonack S., Chen M., Künne C., Sokol A., Günther S., Martínez A., Fleming I., Wettschureck N., Graumann J., Weinstein L., Offermanns S.: Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure. J Clin Invest. 2019 Jun 17;130. pii: 123825. doi: 10.1172/JCI123825. eCollection 2019 Jun 17. DOI:10.1172/JCI123825

PR contact

 

Dr. Matthias Heil

Press officer

Ludwigstrasse 43

D-61231 Bad Nauheim

Tel. +49 (0)6032 705-1705

© 2019 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany