08 September 2021

Summary: The notch receptors: multi-regulators of PAH development

October 25, 2019 (53).jpg

Event summary

The notch receptors: multi-regulators of PAH development” webinar provided further insight into the different Notch signalling pathways. All topics represented current scientific data regarding critical signalling pathways in the development of PAH to provide a better insight of the pathophysiology of this disease and the potential to translate these advances into clinical practice.

The first presentation by Ralph Schermuly (Justus-Liebig University, Giessen, Germany) focused on the role of Notch1 in experimental pulmonary hypertension. Dr Schermuly outlined the importance of the Notch signalling pathway necessary for cell-cell communication, and how its dysregulation can lead to several forms of cancer. In detail, the talk emphasized that Notch1, present in endothelial cells, and Notch3 present in smooth muscle cells are upregulated in human PAH and animal models of PH. Based on these findings, there are potential therapeutic approaches that can improve experimental PH by inhibiting specific ligands and receptors by using neutralizing antibodies or inhibiting cleavage enzymes such as y-secretase.

The second presentation by Marlene Rabinovitch (Stanford University, USA) investigated how the interaction between BMPR2 and Notch1 mediate vascular regeneration in response to injury. Dr Rabinovitch highlighted the importance of smooth muscle cell and endothelial cell interaction to regulate endothelial cell regeneration in response to injury. In detail, the interaction between smooth muscle cells and endothelial cells activates endothelial cell Notch1 in a BMPR2 dependent manner. In addition, Notch1 increases PFKFB3 to induce glycolysis (ATP) and produce acetyl CoA which is required to acetylate histones at enhancer and promoter regions of Notch and MYC target genes which are essential to promote endothelial cell health and regeneration.

The third presentation by Patricia Thistlethwaite (University of California San Diego, USA) focused on the Notch3 signalling pathway, an important driver of the PAH phenotype, and highlighted the potential of this receptor to serve as a biomarker for this disease. In addition, Dr Thistlethwaite reported that a Notch ligand imbalance (high Jagged-1 and low Delta-like-4) cause PAH in humans and rodents. Dr Thistlethwaite tested a proprietary monoclonal antibody that inhibits the Jagged-Notch3 signalling pathway, successfully reversing PH in rodent and pig models of disease. Based on the data presented, Dr Thistlethwaite discussed that monoclonal inhibition of this pathway may be an effective strategy to treat PAH in humans.

The fourth talk by Maya Kumar (Stanford University, USA) focused on how Notch3 expression plays a central role in both neointimal lesion establishment and growth in mouse models of PH.  Dr Kumar demonstrated how chronic perivascular inflammation leads to medial thickening and robust neointimal lesion formation in rodents exposed to house dust mite (HDM), leading to elevated PA pressures and right ventricular hypertrophy. By using lineage tracing, Dr Kumar demonstrated that smooth muscle cells give rise to neointimal formation. These smooth muscle cells use distinct cell behaviours at each stage of artery remodelling. Diving deeper, Dr Kumar identified Notch3 as a molecular marker in a specific subset of smooth muscle cells that generate the neointima. Based on these findings, Dr Kumar showed how blockade of the Notch signalling pathway prevents establishment of the neointima by blocking a transition of vascular smooth muscle cell to neointimal cell, resulting in improved pulmonary vascular pressures.

Summary by Moises Hernandez, UC San Diego, USA

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Pulmonary Arterial Hypertension

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