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I let me just. Ok. Yeah. Ok. Mhm. Mhm. Ok. Hello, great. Uh So hi guys today we're just gonna be going over the vascular endothelium, uh hemostasis and atherosclerosis. So, the Tylers that are gonna be covered today are cardiovascular and respiratory structure and function. So, and basically summarizing the development of the cardiovascular structure and systems and how this relates to function. Um the cardiovascular type of cells and their primary cellular functions. We're gonna be going over vascular disorders, summarizing the pathophysiology presentation and management of these disorders. We're gonna summarize the pathology and pathophysiology of hematological disorders and finally describe the clinical features and treatment options of hematological disorders. So, in terms of the timeline today, we first can be covering the vascular endothelium, then hemostasis, then atherosclerosis and then we're just gonna have a question and answer session towards the end. Um And because of the way metal works, unfortunately, you won't be able to unmute yourself but feel free to type in a message if you have any questions. So what is the vascular structure essentially you have capillary and venules which are formed by endothelium and they're supported by mural cells and basement membranes. In fact, the venules have more pericytes and capillaries are essentially where the exchange of nutrients and O2 occur between blood and tissues. So, as you can see, your artery goes into arterioles, capillaries into venules into the vein and your vascular structure is basically made of three layers in general, except for the capillaries and venules, which we've discussed at the endothelium. These three layers of the cica adventitia, the tunica media and the tunica intima. And as you can see, it's kind of self-explanatory. So I don't see the need to explain that further, but just have a look at that image later on and try to understand the different layers. So, endothelial cells right now, they 90% of the endothelial cells reside within the microvasculature and they basically act as a barrier separating blood from tissues about 1 to 2 micrometers thick and 10 to 20 micrometers in diameter. So as you can see, see, they're really tiny, they're flat, they form a monolayer and they're about one cell deep. They also have contact inhibition and this kind of helps form that monolayer. And what this is is that these cells stop proliferating and dividing when in close contact with each other. Now, the endothelial cells have several functions, uh permeability, inflammation, hemostasis, and thrombosis angiogenesis, vascular tone tissue homeostasis and regeneration. And uh a nice pneumonic to remember that is vit which is just vascular tone angiogenesis for IMIL and then hemostasis, inflammation and tissue homeostasis. So let's talk a bit about endothelial heterogeneity. Now, endothelial cells have structural functional and molecular differences and this is basically based on the organs that are part of. So they have organotypic properties and gene slash protein expression profiles. As you can see on the left side here, they can form three types of barriers, continuous fenestrated and discontinuous. A continuous barriers is what you see in your brain mostly fenestrated. An example is in your kidneys and discontinuous is in your livers. And basically the different barrier structures allow different level of permeability, which is important for different organs. And there's an important type of clustering called cac clustering where the dots represent cells according to the similarity of the gene expression. And the way you can get this gene expression is from single cell RNA sequencing. I hope everyone's following until now, if you have any questions, just feel free to pop it in the chat. So, moving on angiogenesis, right. So, endothelial cells produce angio factors which is vascular endothelial growth factor, which are important for tissue homeostasis and regeneration. Now, the angio profile like the endothelial cell profile is tissue specific and the tissue specific microenvironment also influences the phenotype of the endothelial cells. So, angiogenesis specific type of sprouting angiogenesis is triggered by hypoxia. Now, you can have physiological angiogenesis which is menstrual cycle, wound healing and development or you can have pathological angiogenesis which is causing cancer ischemia and atherosclerosis try to remember these three examples for both physiological and pathological angiogenesis because it may come in handy in something like an SAQ. Now, the ECs proliferate and form new vessels in wound healing. And as you can see here is the process, so essentially when there's hypoxia, you first have the production of angio factors and then the release, then there's receptor binding activation and proliferation. You then have direct directional migration towards the site and then you have extracellular matrix formation. After that, you have steps known as tube formation, loop formation and finally vascular stabilization. So overall, this helps reduce new vessels. Now, in cancer specifically, you have a process called the angiogenic switch. So small tumors tend to receive oxygen and nutrients by diffusion from the horse vasculature. However, larger tumors need new vessels to supply them. Now, these tumor cells secrete angiogenic factors as well and this stimulates new vessel formation by endothelial cells in adjacent vessels. This is known as the angiogenic switch. So the tumor vasculature facilitates growth and metastasis and antiangiogenic drugs are now being developed in combination with chemotherapy for her number of solid tumors. So now you might be thinking what differentiates tumor blood vessel versus vessel. Well, one, they're irregularly shaped and dilated. They have no proper organization into arterioles venues, et cetera. And this makes them very leaky and hemorrhagic. Lastly, they also don't have parasites again, which makes them more leaky. So overall the tumor, blood vessels kind of enable the cancer cells to also spread after the blood vessels are formed. And this kind of just shows how you have a small tumor releasing angiogenic factors. And then you have the formation of new blood vessels covering the tumor. So let's go over an SBA Q, right? What type of clustering is used for classifying endothelial cells based on their gene expression profiles? Feel free to type the answer on the chart. Does anyone know the answer? OK. So let's just go over sura clustering is the right answer. Um Now, I don't see the point in going over the other types of clustering in this case because you probably haven't learned about them. And Jameson clustering is just something I think I invented. I don't actually know if it exists, but yes. So a question as we've discussed before is the right answer. So in COVID-19, your endothelial cells actually play a very important role in terms of the pathogenesis. So after you get a COVID infection, sometimes you can have develop a cytokine storm. This leads to endothelial activation causing a procoagulant switch. So instead of anti-inflammatory antiproliferative antithrombotic, you become prothrombotic in this case. So an activated endothelial monolayer in COVID-19 becomes procoagulant, antifibrinolytic pro-inflammatory. It has impaired barrier function, it becomes vasoconstricted and it becomes prooxidant, all of which is abnormal compared to the normal state of the endothelial cell. And this is what helps with this COVID-19 becoming