This promises to be an amazing #HYPHIP chat!! If you are interested in pulmonary #HTN and cutting edge research on the role that Notch3 plays in it, join us in about 30 min!! Tanja Dudenbostel, MD, FASH, FAHA Guto Montezano The Touyz Lab Hypertension Link to the paper in the 🧵👇🏽👇🏽👇🏽

A1.1. Notch signaling is a key pathway for vascular morphogenesis and function. 4 Notch isoforms are known with Notch3 being expressed primarily in VSMC. Abnormal Notch3 signaling is associated with vascular abnormalities. #HypHIP

A1.2. Notch genes code for a protein that is a cell membrane receptor. Notch3 regulates VSMC differentiation n dis essential for vascular integrity. Notch3 mutations cause CADASIL- small vessel disease of the brain, leading to stroke and premature vascular dementia #HypHIP

A2. 1. Because Notch3 is so important in normal VSMC regulation and function, aberrant Notch3 signaling leads to VSMC alterations including impaired contraction, inflammation and phenotypic switching. #HypHIP

A2.2. Aberrant Notch3 signaling is associated with vascular dysfunction and remodelling, especially of small vessels, important in conditions such as CADASIL and also implicated in PAH. #HypHIP

A3. Pulmonary arterial hypertension (PAH) is a condition when the pressure in the pulmonary arteries is increased. This can lead to heart failure. About 1% of the population has PAH #HypHIP

Q4.1. Indeed clinically, pulmonary hypertension is classified into various categories depending on the underlying cause and/or clinical features. Genes, such as BMP have been associated with PAH. #HypHIP

Q4.2. In our study we used a model of hypoxia-induced pulmonary hypertension, that recapitulates chronic lung disease and/or hypoxemia. The model also has features of PAH. #HypHIP

Q5, PH is typically associated with remodelling, endothelial dysfunction and altered vascular reactivity of the small pulmonary vessels. Many abnormal signaling pathways have been implicated: Ca2+ signaling, Rho kinase, BNP and as we show oxidative and ER stress #HypHIP

A5.2. The novel aspect of our study is that we demonstrate that abnormal Notch3 (gain-of-function) is associated with vascular damage in PH. This suggests a role for Notch3 in PH #HypHIP

Q6.1. Great question. We used a mouse model that has a mutation of Notch3 (the same mutation that causes CADASIL) and exposed these mice to hypoxia. Interestingly, the vascular abnormalities induced by hypoxia were amplified in Notch3 mice. #HypHIP

A6.2. At the molecular level, the methods we used to study Notch 3 were to evaluate the downstream transcription factors, eg He's, HeyL. We also used pharmacological modulators of Notch3. #HypHIP

A7. 1. To our knowledge, our data are novel and contribute new molecular mechanisms linking Rho kinase, ER and oxidative stress through Notch3, as processes underlying vascular damage in PH. I don't think our data contradict previous studies. #HypHIP

A7.2. What is really interesting is that a mutation that causes CADASIL (a small vessel disease of the brain) is also implicated in small vessel injury in PH. #HypHIP

A8.1. We did not encounter any specific experimental challenges, but recognise we have a lot more work to do. For example, we will study the newNotch3-dependent mechanisms in female mice, especially since PAH is more prevalent in women #HypHIP

A8.2. What is especially exciting is that some of the abnormal Notch3-related pathways we identified may be targets for new therapies, eg. - inhibiting Rho kinase with fasudil (which is used clinically, especially in Japan for subarachnoid hemorrhage) #HypHIP

A8.3. So much more exciting work to be done to learn more about Notch3 and small vessel disease, beyond CADASIL. Thanks so much for the opportunity to highlight our study #HypHIP

🔓 For a limited time until August 21, we are offering free promotional access to read the covering editorial for the newest issue of #CJC! 👇 Aging, through knowledge and wisdom: onlinecjc.ca/article/S0828-… 🌐

Rosa Maria Bruno 🔦how the new European Society of Cardiology 2024 ESC Guidelines for Mgt of Elevated #BloodPressure & #Hypertension recommendations for when to start drug treatment & new BP treatment targets ♥️ infographics which can be posted on clinic & waiting rooms etc John William McEvoy @labtouyz

The greatest compliment: freshly released #ESCHypertension guidelines are not boring😎thank you Vass Vassiliou ! John William McEvoy Cian McCarthy The Touyz Lab European Society of Cardiology Dr Anastasia Mihailidou FAHA FCSANZ FESC #ESCCongress