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Shear stress-induced endothelial adrenomedullin...

September 2019

J Clin Invest. 129(7):2775-2791. doi: 10.1172/JCI123825. eCollection 2019 Jun 17.

Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

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

New signaling pathway of blood pressure regulation

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. Scientists at the Max Planck Institute for Heart and Lung Research have elucidated 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 raises 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. Independent research indicated that protein kinase A (PKA) contributes to the regulation of blood pressure through the formation of nitric oxide (NO). However, up to date it remained unclear how the regulation via PKA in endothelial cells actually takes place.

An international research team led by scientists from the Max Planck Institute for Heart and Lung research 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, which can be directly activated by shear stress, 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."

Model of the role of the adrenomedullin receptor and its downstream signaling pathway in flow-induced phosphorylation of eNOS. Laminar flow activates the mechanosensitive cation channel PIEZO1, resulting in the release of adrenomedullin (ADM), which in an autocrine or paracrine fashion activates its receptor consisting of CALCRL and Ramp2, which then through activation of the heterotrimeric G-protein Gs results in the stimulatory regulation of adenylyl cyclase (AC). The increase in cAMP levels leads to activation of protein kinase A (PKA) which phosphorylates murine eNOS at serine 632, resulting in the activation of the enzyme and increased NO-formation. This pathway acts synergistically with Gq/G11-mediated activation of the mechanosensitive complex consisting of PECAM-1, VE-cadherin and VEGFR2, which phosphorylates eNOS at serine 1176 via PI-3-kinase and AKT. The latter pathway is also induced by laminar flow through PIEZO1 activation and ATP release acting on the Gq/G11-coupled purinergic P2Y2 receptor