PDF Medical Lecture Notes

All right, everybody, we're going to go ahead and settle in and get started here. OK, so welcome back. We are having our first lecture of block four, if you can believe that. So we are going to try to tee up in lecture today. I want you to think of it as like the micro environment of the vascular te...

All right, everybody, we're going to go ahead and settle in and get started here. OK, so welcome back. We are having our first lecture of block four, if you can believe that. So we are going to try to tee up in lecture today. I want you to think of it as like the micro environment of the vascular term, because where we're going are some very common disease states, like hypercholesterole, like high blood pressure. And to understand how those disease states are treated and how they come about, we need to understand what the normal environment of the vasculature is. So that's what we'll be talking about today. On Friday, we'll be posting a lecture. It's going to be about some of the unique vasculature around some of what we call special circulations. So we're going to segue from talking about the micro environment to talking about the principle of auto regulation that's really important for things like keeping your brain perfused with blood, despite experiencing, for instance, hypertension. We want the blood flow to the brain to maintain a consistent rate, regardless of what might be the rest of the body is experiencing. So that's kind of where we're going. We welcome, as you probably heard, Dr. Skinner back in. After his clinical case, he'll be giving us an anti- coagulation lecture, as well as an anti-platelet lecture. So let's go ahead and kick things off as we talked about this micro environment of the vasculature. So obviously the vasculature connects to the heart, which is our target organ for January. So right now we are, I want you to think of the conduits of the heart being the blood vessels. And part of the theme of today is comparing the physiology of the arteries versus the veins, and then talking about the unique nature of the capillaries. I think probably the two aspects I think that are sticky, if you will, in this topic would be the concept of compliance when we're talking about blood vessels, because that can seem kind of counterintuitive, depending on how you've learned it in the past. And then the pressure changes that occur over a capillary bed to mostly ensure that fluid is both moved to the interstitial tissue, but then taken out of the interstitial tissue appropriately. If any of you have ever seen in the clinic, DEMA, right, in people's oftentimes feet, legs, has anyone seen that in the past, right? And you can see pitting, where you can physically press in on those peripheral tissues, and that pit will be formed because there's extra fluid in the interstitial space, okay? So we'll talk about how that happens in capillary beds as they adapt to different disease states. For example, heart failure is a very common occurrence that will cause edema. So we've seen one of these before, okay? We're gonna go back over some aspects of different factors that promote vasodilation versus vasoconstriction. And then we're going to kind of walk our way through the general role of arteries and veins and cover some of the big topics like compliance, like resistance, and like the pressure changes, as I mentioned, over a capillary bed. So consider this the vasculature, the light addition, okay? If we're working from the outside, sorry, the inside out here, we have a single layer of endothelial cells. We've talked about vascular smooth muscles, right? And then the next layer, which is mostly in arteries, I should say not only in arteries, and the arterial network are gonna be these elastic fibers, okay? One thing I want us to start thinking about when we hear elastic fibers and an increase in the vascular smooth muscle layer, I want you to think structure. I want you to think rigid, okay? And that means that there is not a lot of compliance. So I'm gonna say that now, and we're gonna come back to it again on a whole slide, but I'm gonna set the stage here for I want you to think of arteries as rigid and veins generally as compliant, and they can change shape. Does anyone know at any given amount of time where most of your blood is? If we were gonna say arteries, veins, heart, lungs, kidneys, we gave you those options. Where do you think most at any given time your blood is? Absolutely, it's in the veins, okay? A majority of your blood volume, somewhere between blood volume is usually between five and six layers, depending on body mass, five and six liters, depending on body mass, four to six or so. A lot of that is in your veins, okay? So I want you to remember that because veins are compliant. They distend, and one of the reasons they can distend is because they don't have these elastic fibers. I think we think of elastic and we think of like stretchy, right, like a rubber band, right? When we're talking about elastic fibers in our blood vessels, we're talking providing support and structure. They are firm, okay? I once heard one of our students make the analogy. It's not like your stretchy waistband on your sweatpants, right? That is a different kind of elastic than the elastic we see in these blood vessels. And then of course you have a layer of collagen and connective tissue on the external most layer. So if we start from, I tend to always go from the heart. So the heart is pumping blood into the arteries, right? And they go from being very wide, rigid vessels, right? Where we have a thick muscular layer. And if we compare that over here to the biggest veins, you notice that the musculature is much thicker. The passageway is actually smaller. It's still big because we're talking about arteries. But relative to their counterpart, the bigger veins, these are rigid structures, right? They need to be, they are receiving blood directly from the heart at high shear rates, right? When you get the chance to see the pig hearts that Dr. Offsoll bring in next semester, the arteries coming right off of the heart, you feel like rubber. It's incredible how strong they are. And then as that blood traverses through this system of smaller arterioles, right, branching off, we start to see slightly thinner muscular walls. And we start to see some of these smaller arterioles are gonna be influenced by the nervous system, specifically the autonomic nervous system. When we get to the capillaries, these are only as thick as one cell, okay? They are very small, but they are extremely numerous, which means they have a really high cross- sectional area. That's super important, because this is the main site of exchange, right? And so the cross-sectional area expands, but the flow through those respective areas slightly slows to allow exchange. We are gonna not go through the oxygen exchange and dissociation curve. We're gonna leave that for our pulmonary system. But that is what one of the main goals is here in the capillaries. And as that blood works its way back up to the heart, something it has to overcome, right, is these vessels that are not as rigid, right, but are oftentimes working against gravity to get blood back to the heart, okay? The venules and veins are gonna have a lot more control from the autonomic nervous system, because if you're in that fight response of the autonomic nervous system, the veins are gonna be tapped to quickly constrict to shut blood back to the heart to make sure that it is perfused and that it can maintain blood pressure. So as we look at this diagram here, this is a classic area versus velocity look at when we're talking about, just as we talk about here, if we go arteries, arterioles, capillaries, venules to veins, we see that the velocity, as we described, coming off of the heart into the arteries is very high. The cross-section of those really wide arteries is actually not that great when you compare it to the numerous arterioles and capillaries, which is why that cross-sectional area actually goes up, right? We tend to think of arteries as big, but there's not that many really, really big arteries, but there are a ton of arterioles and capillaries when we start comparing them head to head in terms of their area. And as we mentioned, a characteristic of shear rate is that that velocity is going too slow as we start to work our way, the blood works away through the capillaries, and it will pick back up to some of these, by some of these venule pumps that we'll talk about. These are kind of like valves within your venules to help continue to move that blood back to the heart. It also is aided by a lot of your veins are actually in between, particularly in your legs, they're in between muscles. And so literally why we encourage the elderly to take moderate walks is to help with circulation especially, because that mild walking and the stimulation of leg muscles really helps maintain that more of a consistent blood flow. So that capillaries, we want it to be the slowest, but the biggest area to facilitate that site of exchange. So I wanna make one modification here that the updated textbook doesn't have. So we're all clear here. Okay, I want you to cross out this first word here, capillaries and arteries here, okay? That is an error that we caught as we work through this diagram. The rest of it, the rest of it's accurate, but the examples there are inappropriately flipped. So let's talk about compliance. This is one of those sticky subjects that I mentioned is one of the things that I always tend to remember is can sometimes be a hurdle of understanding in this particular content. So the idea of compliance is the degree to which a vessel can distend, right? And when you hear distend, I want you to think veins, okay? Veins distend because they don't have that elastic layer that helps ensure rigidity like in arteries, okay? So arteries are considered to have low compliance, right? They're rigid. So in this example here, if this has high amount of pressure, let's say this is the aorta, right? And that blood is coming through there at high pressure, high volume. It has very low compliance because it's going to maintain its shape and integrity compared to, if we were to compare this to a vein, which is considered to have very high compliance, right? It distends very easily, okay? So if the pressure is increased in venules, their response is to distend, okay? So this makes sense as to how most of our blood at any given moment is in the venule system. It's because it can comply and almost act like a reservoir to be able to shut blood back to the heart or elsewhere as needed. Okay, so these larger arteries are full of the high pressure system. What we see here, we are not going to cover blood pressure yet. This is just conveying general sense of systolic and diastolic variation. But generally as blood works its way through the vessels, it's generally the pressure is going down, okay? To make sure that blood comes from the heart and gets to the capillaries. The site of the capillaries it's then thought of as the venule's job to get that blood back to the heart. When this goes awry, as we will use a couple examples of, like, sudden loss of blood, what happens in hemorrhaging, how the system accommodates versus the opposite response, which would be when there's a change in pressure in the venule system due to heart failure. Two of the clinical examples we're gonna use as to when this pressure system gets out of whack and how those vessels respond to try to, at the end of the day, maintain pressure, okay? So the pressure gets out of whack. It oftentimes is either gonna go into the interstitial fluid like an edema, or if it gets very low like a sudden loss of blood, it's going to draw as much fluid from the interstitial system into the venule system to try to maintain blood volume as blood is being lost. So some of the things that make small arteries and arterioles unique, there we go, okay. I don't think we missed much. So what makes these smaller arterioles unique is the ability to serve as almost these valves. Like if you think of these faucets and these cartoons here, where local factors, okay, independent of blood flow of cardiac output can affect the perfusion to these smaller arterioles. So this could be, for instance, if there's an abundance of lactic acid. For example, during exercise, this will cause these small arteries and arterioles to allow more blood to be shunned through these smaller arterioles. What we're seeing here is an example of turning it off or down to where, normally if blood is perfusing through these tissues here, we can turn the respective volume up by either local or nerve, in some examples, nerve control. But also in the, for example, in the sympathetic nervous system, we can turn the flow down. And this happens at the level of these small arteries and arterioles. This relates to receptors that we've learned about before, right? Alpha-1 is vasoconstriction, beta-2 is vasodilation. So that is the how through the sympathetic nervous system, these faucets, if you will, can be adjusted to meet the metabolic needs of these tissues. So here's the highlights of our capillary beds, okay? Which of course you'd think of as the site of exchange, right? And where they're very thin-walled and the blood flow and pressure is gonna be pretty low, relative to other areas of the body. There are two main ways of passage through capillaries. There's essentially in between these endothelial cells and there's what's characteristic to capillaries is these fenestrations. These fenestrations are gaps in layers to where very small amount of fluid and blood cells can pass through. So as we look at this site of exchange here, the main role, of course, is to load up on oxygen when we're around the lungs and offload waste, right? And so this, of course, is facilitated by red blood cells, which we are not going to spend a lot of time talking about in detail in this section. So the other ways outside of the main fenestration and simple diffusion that cargo, if you will, can be moved across these blood cell layers is through things like pinocytosis. That would be more like things that are the size of antibodies, pretty large. Bulk flow is what we're going to focus on today, okay? Because bulk flow is influenced by pressure. So this is the most common way to move fluid either into the interstitial space or pull it back into the capillary bed. So we're gonna talk about the respective pressures that are at play in capillaries that are going to essentially tip the balance. If we're in homeostasis, it's going to even out, where on the arterial side of the capillary bed, there's going to be the same amount of movement of fluids into the interstitium as on the venial side of the capillary, which means there's going to be the same amount of recovery. We are not, as we indicated on that Draw It to New It module, we're not going to spend any time talking about the role of the lymphatic system. But to put into context, the lymphatic system related to capillaries is an additional release valve that can help with maintaining this system of equilibrium of the pressure change across capillaries to support an equal movement. So that at the end of the passage through the capillaries, there's about an equal amount of movement into the interstitium and out of the interstitium. And then there's, of course, simple diffusion by either those fenestration or pores, or simple diffusion across those endothelial cells. So let's spend some time going through this diagram here, which I tend to refer to as the H diagram, because that's what it looks like. But I want to point out a few things, okay? So as we look at this diagram here, which is conveying the pressure change across a capillary bed, basically stretched out one little capillary bed to get across the principle of the pressure changes that ensure that there's mostly an equal amount of fluid moving into the interstitium and then fluid coming back into the capillary across the capillary bed. So let's look at a few things here. So we see we have arterioles. So essentially this tube here is conveying that this is arteriol. This side of the H diagram is considered the venule. And capillaries, as you all can appreciate, don't look like this. This is a very simplified version of a capillary, right? We're basically, what's blood doing? It's coming here, it's going here, and it's going there. It's what this is supposed to represent, okay? Blood encounters pressure changes as it makes this route from the arterial through the capillary to the venule. What we're showing here, this vector, especially this one right here, okay, across the middle, this is a theoretical vector to understand the pressure change across these capillaries, okay? So what's less important is the actual number of pressure because at any given person, these pressure changes might be a little bit different. But let's note, on the arterial side, it's higher than on the venule side, right? The venule side, if we're looking here, this pressure might be about 15 millimeters of mercury versus 35 on the arterial side. This is the dynamic pressure change over a short distance for blood to encounter, okay? So there's two forces at play that we want to talk about. What's referred to as PC and pi C, okay? What we're talking about right now, which makes this a little bit easier to understand, is that across any given capillary bed that we're talking about in this unit, pi C, or the amount of pressure that's favoring pulling fluid back into the capillary is constant, okay? This relates back to a concept we talked about when we talked about volume of distribution in drugs. Does anyone recall the main contributing factor in blood that affects volume of distribution of a drug? Yeah, you remember Abby? Yes, albumin content, okay? The amount of albumin is the main driving source of this plasma colloid osmotic pressure. Think of it like a magnet in the blood that is pulling fluid, especially, into the blood, okay? In the capillaries we're discussing this unit, it's going to be constant, which is why we have a dashed line across this diagram, okay? So that makes it simpler. Then when we get into our renal section where the albumin content varies, okay? So in a typical capillary bed, the same amount of albumin is coming through there. It's the main source of pressure, or magnet, if you will, of pulling mostly fluid back into the capillary. We're going to always compare that to the PC, which is the capillary bed's hydrostatic pressure, okay? This generally is the amount of pressure that is favoring moving fluid out of a capillary bed, okay? So we're going to be talking a lot about, is PC greater than pi C, or is pi C greater than PC, okay? As we look at this diagram, remember, I'm going to say it again, this line that we're going to talk about, this is a theoretical vector. It's just conveying the pressure change from the arterial to the venule across this capillary bed. Okay? And as we put this into context with fluid movement, what we see here is when we're comparing on the arterial side, PC, right? PC, if we would draw a line here, we'll call that 33, maybe, Blood on this side of the arterial side of the capillary, the pressure is higher than pi C, which is in this diagram about at 25, okay? So if PC is greater than pi C, that means it's going to favor moving any fluid into the interstitium. But notice, as we talked about, there's a dynamic pressure change, right? As blood then traverses across here, okay? To where if we come over here on this side of the capillary bed, and we just pick a spot over here, right, what happens now? We'll call this 22, okay? Now, pi C is greater than PC, and that is the pressure change on the venule side of the capillary bed that is then pulling, or pushing, if you will, fluid back in to the capillary bed. I'm gonna pause for a moment so we can all look at this together, and I wanna make sure if some people are conferring with your seatmates there about what this means. So what we're showing here would be an approximate equalization, okay? In a normally functioning capillary bed, absent of disease or trauma. This is roughly what's gonna happen. It's about equalizing, okay? And so if numbers are your jam for remembering this, that's kinda how we went over it on the left here. If you prefer just simply which is greater, these bullet points are gonna help you out, right? So we're just focusing on which is greater. If PC is greater, that's going to be favoring fluid movement into the tissue. If pi C is greater, it's going to be favored moving fluid into the capillary. Questions so far? Yeah, Ken. Is the volume of fluid exchange the same throughout? So we are assuming that this is relatively imbalanced. So are you talking about whole blood volume completely or within the capillary? Yeah, because on the diagram it says any excess is removed by lymphatic system. I'm just wondering where that excess is coming from. Yeah, he's pointing out what's down here. So under normal circumstances, if there is a slight variance, that's when our functioning lymphatic system will even it out. It's almost like a buffer for this system, okay? So beyond that, you don't really need to know much, okay? But that generally over the normal capillary bed, it's about an equal exchange. If there's a little more, then the lymphatic system will handle it, okay? We're then going to use two very different states to see when it gets disrupted what happens, okay? But focusing on these principles right here will tell you each time what's going to happen, okay? And it's the appreciation that over this capillary bed, it's the same blood, right? But it's encountering vastly different pressure as it works its way from the arterial side of the capillary bed to the venial side. Any other questions before we move on? Okay, all right, so let's use examples like we have in the past of the exact, like opposite ends of the spectrum that could affect this capillary bed. So we're gonna use, let me get more normal color here, we're gonna use an example of like hemorrhage, sudden loss of blood volume, and we're gonna use heart failure, okay, generally. You don't need to know, we'll do a deep dive on heart failure later. Right now, we're just gonna understand that if the heart is failing, that means there's gonna be a change in pressure because it's not contracting appropriately. So let's start with a sudden loss of blood volume. So if we replicate those kind of simplistic H diagrams, we've got the arterial side here, the venial side here, we'll call this about 35, we'll call this about 15 or so, just the idea it's a gradient, right, running alongside here, okay. So if we have a sudden loss of blood volume, which side, if you will, of our circulatory system, is that going to affect most? Arterials or veins in terms of pressure change? Okay, we got someone say arteries, okay. What else do we think? Generally, arteries are gonna be the last affected because they're closer to the heart, and so they're going to be less susceptible to pressure changes, as long as the heart is still contracting, okay. So in this example of sudden blood loss, the drop in volume is going to be mostly experienced on the venial side, okay, because that's where most of the blood is, and remember, it's got a high degree of compliance, okay. So if we call, we'll draw our little theoretical here, right. Let's say in our first diagram, it was like roughly here, right. On this one, let's even extend this so we can exaggerate the example here. Let's say that blood pressure, blood volume drop is now down here, okay. So our theoretical diagram is going to look, let me make sure I draw this vector right, ooh, like this, okay. So we, on all of our examples, we're saying that pi C is staying the same. We'll leave the renal unit to talk about when it's different, okay. So take a moment, take this in, all right. The cheat sheets are below, but, but. So when we see this change, essentially a drop in venial pressure, okay, on our diagram here, so let's say it goes to 10, whoops, sorry, it's not calibrated, 10, something like that, okay, is where this is, okay. There's still gonna be movement here, but if we're talking about a balance, there's going to be a ton of reabsorption on the venual side of the capillary bed. So someone described in your own words why our body accommodates like this. How does this maybe help a sudden loss of pressure due to blood loss? What do we think? Yeah, what do you think, Abby? Okay, so with the goal of trying to make, so with a sudden loss, right, of blood volume, we need to, where the body needs to try to ensure that the heart has blood to contract around, right. So the idea here of this dynamic pressure change to where because pi C is going to be much lower on the venual side, it's going to tip the balance in favor of more interstitial fluid being pulled back in to the venual side of the capillaries, okay. This is with the goal of trying to create more fluid in blood due to this sudden loss of venual pressure, okay. That doesn't mean it's gonna fix it. This is just the body's response is to pull fluid from the interstitial tissue to try to combat the loss of blood volume. So the opposite of that occurrence is how we have edema in people that experience heart failure, okay. So if we set up a similar system here, five down to 12 roughly, right, this is gonna be usually constant. Here's our venual, okay. Now the veins accommodate heart failure the opposite way, okay, so if the heart is, for a number of reasons, the heart is underperforming, okay, which means that it's not contracting efficiently, which means that blood is not moving through the circulatory system smoothly or efficiently. This also disproportionately affects the veins, okay. The veins start to essentially get backed up with blood, okay, the pressure starts to rise in the venial system because the heart is underperforming, okay. We're gonna generalize what's occurring here. So if the heart is failing, the venial pressure goes up. So if normal is here, venial pressure is going to get much, much higher to create a system that looks more like this to where there is way too much fluid being pushed into the interstitium, okay, due to this increase in pressure in the venules. This is where the, it's now more of outdated term. They used to call it congestive heart failure. There's new term, newer updated terminology now, but the congestive aspect comes from venial pressure rising, which will then cause to try, in an attempt to alleviate this pressure is trying to draw fluids out of the capillary bed, which then will, depending on if it's right or left heart failure, will land in different areas of the body, okay. This is a classic situation of how edema would, could be pulmonary, could be peripheral, would result through the capillary bed. Questions before we move on? So the take homes here are understanding PC versus Pisces, okay, in normal circumstances, and then applying it to these two examples to understand how either sudden loss affects venial pressure and how heart failure affects venial pressure and the response then of the capillary beds with to those pressure changes, okay. All right, so as we continue to work our way for thinking capillary beds, now we're gonna move blood back up to the heart. This is, of course, the role of the very accommodating venial system, right. And this is what these respective valves look like, okay. They're just simple flaps to try to help prevent backflow. And if we're putting a percentage on it, somewhere between 65, 70% of your blood volume at any time is going to be in your veins. And so this is thought of as a low pressure system. Because it's a low pressure system, it tends to, just like it's a reservoir for blood, it tends to be affected by different states, whether it be blood loss, sudden blood loss, or instances of heart failure. And here's what a diagram might look like to illustrate what's considered a venous pump, okay. This is unique to the venial side of our circulatory system in that veins can be uniquely positioned in between muscles, skeletal muscles, to help promote the movement of blood through the venial system. Another, I wouldn't say it's unique because we do see veno constriction on some of the arterial sides, but the way it's done is different, okay. So remember, on the arterial side, we talked about that there's almost like valves, right, that can either turn up or turn down the perfusion of blood through arterials. In the venial side, this is mostly done by the nervous system. There's not a lot of local factors that are going to influence veno constriction, for example. It is done through the nervous system. And so what we're seeing here is how that's accomplished. If we look at a cross section of a venial here, notice that these are collagen, right, there's not elastic there, but collagen, and if we have a nerve that innervates it, there's going to be a response to an increase in that blood flow. So let's say the pressure goes up in like heart failure, for example, something causes an increase in the pressure in the venial system. There's going to be a response by the sympathetic nervous system. And what it will do is as these collagen filaments start to expand, that's going to cause the sympathetic nervous system to signal for contraction. So it's a system that is going to distend, but also can be contracted through the sympathetic nervous system. So this could also be an example of how in a fight versus flight response, how if there needs to be more blood to be moved quickly from the venules to the heart to support a fight response, this is how it would happen. So now we want to talk about from the blood perspective, how blood is moving through this vasculature system. And certainly flow is going to affect the movement of blood, but the main factor is resistance. So compliance, resistance, and those capillary diagrams are kind of the big three topics of today's content. And what we're looking at here is flow, this is supposed to be an arrow essentially through here. And in very healthy blood vessels, this endothelial coat will act almost like a sheer layer to promote smooth blood, red blood cell moving through this blood vessel. It's when we start to talk about an occurrence of increasing amounts of plaque or a really unhealthy endothelial layer that we start to see what we call more turbid flow, which can be very problematic. So this resistance is a measurement of how resistant the vasculature is to flow. And there needs to be a certain level of resistance to make sure blood is moving through any of these blood vessels. So let's look at what this law. So Poiseuille's law, we're gonna talk about in the number of just the factors. So there's a couple of factors we want you to be aware of of how resistance is essentially, or flow is assessed in vessels. So the primary determinant of the level of resistance is just simply the radius of any blood vessel. And that's a factor R. The length is inversely related, which is why if you're calculating using Poiseuille's law, we are not going to calculate, we are going to expect you to understand these factors and how they influence the flow resistance, the amount of resistance. So understanding that vessel length is inversely related, we can see that in the calculation, it's in the denominator. And then the third main factor we want you to be aware of is blood viscosity, okay? Which can be influenced by a number of factors. So how essentially, how sticky or not is the blood? And certainly disease states can affect this, hydration status can affect this, but it's these three main factors that are going to determine the amount of resistance or the change in resistance in a blood vessel. So we see what the goal here is this very smooth flow, okay? And that the endothelium is healthy, that it is proportionately wide enough to allow red blood cells to go through in a streamlined fashion. What can occur in disease states, either unhealthy endothelium, sometimes valve replacements of the heart can also cause this as well, is what we call turbulent flow, okay? Where red blood cells for a variety of reasons are literally just bouncing off the side of the vessel walls. What do you think that this could cause? There's a lot of albumin in there, all right? We've got a lot of things that are sticky factors related to blood, okay? And so it's advantageous for health for it to be a streamlined flow of blood cells. We started seeing too much of this, and some of those red blood cells can start sticking to the endothelial layer. That can eventually, along with other factors we'll talk about, can start to cause plaque formation, which can also break off, like a thrombi, which is one of our clinical examples here. So these, if a red blood cell flow is not streamlined and we have too much turbulent flow, this is where we can see thrombi form, which not only are dangerous when they're attached to a vessel, but especially can become lethal when they dislodge, because then they can lead to sudden blood clots. So the most common instances of this is like AFib, atrial fibrillation, which we'll go over in January, but simply put, it's the top of the heart contracting faster than the bottom, okay? Which is going to cause turbid blood flow, because we've got a mismatch in contraction. Or as I mentioned, heart valve replacement. So going from something that looks like this, maybe they have an underlying congenital condition that requires heart valve replacement, to then putting in a heart valve that looks like this, that is great for it to promote heart health. But these little factors can cause platelets to aggregate, which can be a big problem. This should look familiar from Dr. Skinner's clinical case, right? DVT, it's where we have deep vein thrombrosis here on the left. So with the time we have remaining, let's continue to think about the local or microenvironment of these blood vessels. Because diseases and the treatments that we are going to cover are going to happen in this more microenvironment, right? We kind of walked through the general overview and roles of all the way out of the arterials, through the capillaries, and through the venules. Now let's talk about some of those more local factors, okay? And so we can classify them into vasoconstrictors and vasodilators, okay? The vasoconstrictors, in my opinion, are pretty straightforward, right? They're mostly neurotransmitters or factors that are going to cause vasoconstriction. The vasodilators are a little more nuanced, okay? Where you have, well, revisit nitric oxide, for example. But the one that's really important to put into context is this idea of change in tissue metabolism, right? Where the easiest example is always exercise, right? Where you have an increase in metabolic rates, temperature that is going to start emitting factors, not necessarily, and all of them are toxic, but factors that are going to need to be rinsed out of that tissue and carried away from that really metabolically active tissue. So isn't it clever that our body uses this adaptation, those same signals are going to induce vasodilation of these smaller vessels to allow an easier washing away, if you will, if it causes vasodilation. There's more blood that's gonna be coming through, which will help address the metabolic needs of the tissues that they support. And then another factor would be a decrease in oxygen, okay? So a decrease in oxygen is going to be a stimuli, an act as a vasodilator, okay? So as for some type of hypoxic condition arises, the body's response generally is to vasodilate, to try to address, okay, if there's not enough oxygen, we need more red blood cells to facilitate and address this status of low oxygen. So let's look a little bit more closely about the two mechanisms, okay, of local mediators of vasocontrol. So you can classify them generally as metabolic or myogenic, okay? So if we look back at this little silly cartoon with the faucet example here, and these are supposed to be indicative of very metabolically active tissue that is surrounding these vessels. And you can see what's indicated here are a variety of factors that are given off by tissues that are experiencing a high rate of metabolic activity. So lactate, hydron ions, potassium, all of these are local byproducts, if you will, of metabolism that are going to cause vasodilation, to help, in essence, kind of wash away, if you will, and bring in more red blood cells to diffuse away these byproducts of metabolism. Myogenic, okay, note, this is a note from a, I put in here, this is not intuitive, okay? We have some responses in our body that don't necessarily make sense. The metabolic one totally makes sense, right? We've got increase in the like lactic acid, we need to flush the system with it. This response is not as intuitive. It's known as myogenic, okay? So resistance vessels, like we've talked about, are going to have almost a reflex that has been shown. They're going to constrict when there are local increases in intramural pressure, okay? This seems counterintuitive because if pressure goes up, you would think, oh, we want to dilate to help address this pressure, okay? It makes a little bit more sense when we start to think about where these, where this vasoconstriction happens, okay? So if we have an increase in pressure or blood flow in a bigger vessel, this vasoconstriction tends to happen in these smaller branching, vessels. The way I tend to think about it is it's kind of a self- preservation move by our body because if we would continue looking at this vessel, where is it likely going? If it's getting smaller, if it's a smaller vessel. It's going to get a capillaries, right? What do we not want in the capillaries? A sudden change of pressure, right? Or an increase in flow is going to suddenly change those dynamics like we talked about in our H diagram, okay? So I encourage you to try to remember it like that, that this is a reflexive kind of preservation move by these smaller arteries to say, okay, we have an increase in a bigger blood vessel in pressure, we don't want that pressure to affect some of our smaller arteries and capillaries, okay, but this certainly, oops, sorry, I thought there was another point there, certainly is counterintuitive to the factors that we just talked about. So this event is called myogenic versus metabolic. So the time we have left that we get to review and add a little bit more detail into some of the topics that we've talked about in the vascular smooth muscle vessels. So remember when we were focused mainly on this layer here of smooth muscles, right? And we talked about how if there's increased and available of calcium, that causes vasoconstriction, right, because we have calcium that will promote smooth muscle contraction, where if we have a decrease in calcium, that's going to facilitate vasodilation. And that goes back to the mechanisms of how the smooth muscle contracts or relaxes. So if we go back to these diagrams here, right? Some of this is review and some of it, we're just adding a little bit more detail as we tee up here for some disease states. So in the normal endothelial control of blood flow, things like nitric oxide, as we've covered before, those are going to act as vasodilators. They're going to minimize the availability of calcium, which will induce relaxation, which will cause vasodilation. There are, so this is one mechanism that is thought of as a control, right? Modifying nitric oxide availability is the source of a number of intracellular signaling pathways that are going to affect nitric oxide to then have an overall effect of vasodilation. So what I just want to point out here is we're not going back through all the intracellular signaling, right? But there are many factors like acetylcholine, for example, that is going to through intracellular signaling in the endothelial cell increase the availability of nitric oxide, right? This is in the endothelial layer of a vessel. And as that nitric oxide increases, the signaling will take place in the smooth muscle, right? That's the layer next to it, which will induce muscle cell relaxation and then respective dilation, okay? So the key points here are acetylcholine, which we've talked about, nitric oxide, and then nitric oxide signaling through its respective network to induce muscle relaxation. Okay, so what I'll do, because I realize we're at time, I will, on our recording for Friday, I will start here on our prostaglandin slide, which hopefully you recall can be, it can do both, right? It can cause vasodilation or vasoconstriction. So we will have office hours on Friday ahead of our research day in the afternoon. So if you'd like to review any of this content, stop on by on Friday. And I look forward to seeing you around between then. Thanks guys.