Modulators of the Hypoxia-inducible Factor (HIF) pathway and their impact on the pulmonary vasculature in humans

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The blood vessels within the lungs are unique. In other parts of the body, when there is not enough oxygen present, the blood vessels increase in size (dilate) to deliver more blood to the organs. However, in the lungs, they narrow (constrict). This is because continuing to send blood to an area of the lung that does not contain oxygen is inefficient - blood is diverted to parts of the lung that can continue to pass oxygen into the bloodstream.The blood vessels of the lung react very quickly, and we can see this using ultrasound of the heart - as the vessels constrict, the blood pressure in the lung increases. Eventually, this increase can actually affect how the heart functions and how well it pumps. These blood vessels can constrict more effectively under certain circumstances. For example, we know that when a lack of oxygen (termed hypoxia) continues for several hours, the blood vessels are able to react more strongly i.e. they are 'primed'. This means the blood pressure in the lungs increases to a higher level.Why does sustained hypoxia make changes in the body like this? The answer is due to an important 'signaling pathway' - a cascade of steps that results in genes being switched on from our DNA. These genes have many different effects, and one of these is to make the blood vessels in our lungs more sensitive to hypoxia. This signaling pathway is incredibly important - indeed, the scientists who discovered it were awarded the Nobel Prize in 2019. It is present in all of us, and in all animals, and it orchestrates the changes that happen to us when there is not enough oxygen present e.g. at altitude, or due to lung diseases, or locally in different types of cancers.We now understand a great deal about the different components of this signaling pathway - there are several steps that are very important. When these steps go wrong due to genetic diseases, or when they are manipulated by drugs, changes happen in how the body functions. We know, for example, that there are people with genetic conditions that mean that the pathway is always switched on, even when there is plenty of oxygen present. Scientists discovered that the blood vessels in the lungs of these people constrict very strongly in hypoxia. This tells us that this signaling pathway plays an important role in controlling the blood pressure in our lungs.This is significant, because there is a drug that is licensed in many countries, including in the UK, that switches on this hypoxia signaling pathway. This drug is used to treat the anaemia (low haemoglobin and low red blood count) that accompanies long-term kidney disease. By switching on the hypoxia pathway, this drug (called Roxadustat) switches on the gene for EPO (erythropoietin) and tells the body to make more haemoglobin and red blood cells. This is a good thing, and the drug has been shown to be safe.However, we don't know what this drug does to the blood vessels in the lungs. Based on what we know already, we would expect that it would make them react more strongly when there is a lack of oxygen. This is important - many people around the world will be taking this drug for a long time, and if they become unwell then there will be a lack of oxygen and this could cause high blood pressure in the lungs, and even affect the heart. This can even be relevant during air travel, since the air pressure in the cabin of the plane is a bit lower than normal, and so there is less oxygen to breathe. Most people don't notice this, but it could be important for people taking this kind of drug.Therefore, the aim of this research study is to give Roxadustat to healthy volunteers and measure the blood pressure in the lungs when they are breathing normal air, and when they are breathing in less oxygen. This will tell us what effect the drug is having on the blood vessels in the lungs, and help guide scientists and doctors in the future.