Trait: Nitric Oxide and Blood Flow

Dr Haran Sivapalan


February 27, 2019

The importance of blood flow

Like other complex, multi-cellular organisms that inhabit the living world, humans are made from an assortment of different cells, all of which require oxygen and nutrients to survive and function properly.

More primitive organisms, such as jellyfish and sponges, which only contain a single or few layers of cells, can simply obtain oxygen and nutrients directly from their surrounding environment through a process of diffusion. They also use the same process to get rid of waste products (e.g. carbon dioxide).

This strategy, however, gets trickier as organisms become larger and more complicated. To solve this issue, animals such as fish, reptiles and mammals (including humans) have evolved circulatory systems that distribute oxygen and nutrients to different cells using a specialised transport fluid: blood.*

Animal circulatory systems typically consist of a pump (the heart), tubes (blood vessels – arteries and veins) and an organ to take in oxygen and expel carbon dioxide (the lungs [or gills in fish]). In humans and other mammals, blood is pumped by the right-side of the heart to the lungs, where it becomes oxygenated. It then returns to the left-side heart, where it is pumped onwards through arteries to supply tissues and organs with oxygen and nutrients. The flow of blood to tissues also helps to remove any metabolites and waste products that may have accumulated.


  • Humans have evolved a circulatory system because we cannot rely solely on diffusion to transport important molecules around the body.
  • Blood flow is required to deliver oxygen, nutrients and other key molecules (e.g. hormones) to organs and tissues.
  • Blood flow is required to remove waste products and metabolites away from organs and tissues.

* Interestingly, the cells of the cornea (the transparent front layer of the eye) are the only part of the human body not to have a blood supply. Instead, these cells obtain oxygen by diffusion from the outside atmosphere, while absorbing nutrients from fluid inside the eye.  

Why do we need to increase blood flow to different parts of the body?

Suppose, instead of passively reading this blog, you suddenly started doing a set of bicep curls. Your biceps muscles are now working much harder than before and therefore require more oxygen and nutrients (e.g. glucose) to continue contracting.

In other words, your exercising muscles have greater energy demands. To meet these increased energy demands, your body will have to supply your muscles with more blood.

Muscle contraction also generates various waste products, such as carbon dioxide, lactic acid, ADP and magnesium ions. If these waste products are allowed to build up, they can change the immediate environment of muscle cells, negatively affecting their ability to contract and function efficiently. Consequently, your muscles also require increased blood flow to remove and transport away such waste products to either be excreted or further metabolised.

Given the changing activity of different tissues over the course of a normal day, your body is continually playing an intricate balancing game where it matches blood flow to the energy demands (and metabolite production) of various tissues.

During intense exercise, studies suggest that blood flow to working muscles increases by as much as 50 to 100 times!


  • Tissues and organs with greater energy demands require a greater flow of blood.
  • Exercising muscles require greater blood flow to provide oxygen and nutrients for muscle contraction.
  • Exercising muscles also need greater blood flow to prevent the build-up of metabolites and waste products.

How do we increase blood flow to exercising muscles?

There are two main ways we can increase blood flow to exercising muscles. Firstly, we can simply get the heart to pump at a faster rate. If you suddenly perform 20 push-ups and then take your pulse rate, you’ll notice that your heart rate has significantly sped up. This happens in order to supply your working pectoral, triceps, core and other active muscles with blood.

Despite this, while a faster heart rate will certainly increase the amount of blood flowing through arteries at any given moment, it does not necessarily ensure that this blood is going to where it’s most needed – in this case, exercising muscles.

This is where your blood vessels come into play. The second way your body can increase or decrease blood flow to a particular organ or tissue is by respectively widening or narrowing the arteries supplying that organ (or tissue).

How does it do this? Within the walls of your arteries (and some veins) are rings of a special type of muscle called ‘vascular smooth muscle.’ You’ll learn more about this muscle type in a future blog. When vascular smooth muscle contracts, the blood vessel narrows and the lumen (the hole in the middle of a blood vessel) gets smaller, allowing less blood to flow. We call this process: vasoconstriction.

By contrast, when vascular smooth muscle relaxes, the blood vessel widens and the lumen enlarges, allowing more blood to flow through. This process is called vasodilatation. There are several different mechanisms by which vasodilatation is triggered, some of which involve an important molecule called nitric oxide (NO).


  • Your heart rate gets faster to increase blood flow to exercising muscles.
  • You widen blood vessels (a process called ‘vasodilatation’) to increase blood flow to exercising muscles.
  • Nitric oxide (NO) plays a key role in vasodilatation, especially during exercise.
smooth muscle layer

What is Nitric Oxide (NO) and where is it produced?

Nitric oxide is a small signalling molecule produced by various cells in the body, including nerve cells in the brain (neurons), immune cells and cells found in the lining of blood vessels. With respect to increasing blood flow to organs and tissues, it is this latter group that we are most interested in.

Rather than being one uniform structure, the walls of your blood vessels are composed of different layers. As previously mentioned, one of these layers (the middle layer) contains vascular smooth muscle. The innermost layer, i.e. the one in direct contact with the blood flowing through the lumen, is called the endothelium. The endothelium lining your arteries and veins is composed of special cells called vascular endothelial cells - it is these cells that produce and release nitric oxide.

As will be explained shortly, nitric oxide diffuses from vascular endothelial cells to the middle layer of blood vessel walls, where it acts on vascular smooth muscle cells to cause vasodilatation. In this regard, we can classify nitric oxide as a vasodilator substance - it widens blood vessels and increases blood flow.


  • Your blood vessel (arteries and veins) walls are made from different layers of cells.
  • The inner lining of your blood vessels (called ‘endothelium’) is made from vascular endothelial cells.
  • Nitric oxide is produced by vascular endothelial cells.
  • Nitric oxide is a vasodilator molecule – it widens blood vessels to increase blood flow.

How is Nitric Oxide (NO) produced?

Nitric oxide is made from the amino acid, L-arginine. As a non-essential amino acid, your body can produce L-arginine itself, but it is also found in various foods, including: turkey, seafood, spinach, soybeans, lentils, peanuts and pumpkin seeds. L-arginine is also available as a supplement.

To make nitric oxide, your vascular endothelial cells produce an enzyme called Nitric Oxide Synthase (NOS), which converts L-arginine into nitric oxide. For the NOS enzyme to produce nitric oxide effectively, it also requires other molecules (called cofactors). One of these cofactors is called BH4 (tetrahydrobiopterin).

A by-product of NO formation is L-citrulline, which, like L-arginine, is another amino acid. Interestingly, L-citrulline can be recycled back into L-arginine, which can then be used by NOS to produce more nitric oxide. This is why some athletes take L-citrulline supplements.

It’s also worth noting that our blood vessels produce two different forms of NOS. One form is continuously active and constantly producing nitric oxide. We call this form: constitutive NOS (or cNOS / NOS III).

The other form of NOS is largely inactive during normal circumstances, but gets activated during inflammation. We call this form: inducible NOS (or iNOS / NOS II).

When it comes to promoting vasodilatation and blood flow during exercise, we are mainly concerned with the cNOS / NOS III form. Hereafter, when we refer to NOS, we are specifically talking about cNOS / NOS III.


  • Nitric Oxide Synthase (NOS) is the name of the enzyme that makes NO.
  • Nitric oxide (NO) is made from the amino acid – L-arginine.
  • L-arginine can be made from another amino acid – L-citrulline.
  • NOS requires other molecules (cofactors) to work – one of these is BH4.
  • There are two types of NOS – cNOS or NOS III and iNOS or NOS II.
  • cNOS (NOS III) is responsible for producing NO to dilate blood vessels during exercise.

What causes Nitric Oxide (NO) production?

Imagine again that you’re performing 20 push-ups (or if you have the time and inclination, you can actually do these in real life!). As established, your heart will pump more rapidly and forcefully, causing blood to flow through arteries at a faster rate.

As blood flows more quickly, it actually creates frictional force against the inner lining of blood vessel wall. This force, known as shear stress, stimulates vascular endothelial cells (by causing calcium to enter these cells) and activates the NOS enzyme.

The activation of NOS causes the rapid formation of nitric oxide (NO), which leads to the widening of the blood vessel (vasodilatation) and further enhancement of blood flow. This is a very nifty mechanism for quickly and significantly raising blood flow to exercising muscles.

Another thing that occurs when you’re performing push-ups (or any other exercise for that matter) is that your working muscles will produce a molecule called adenosine. Located on the surface of your vascular endothelial cells (that line your blood vessels) are special adenosine receptors. When adenosine binds to these receptors, it also activates NOS and stimulates the formation of nitric oxide (NO). Again, this leads to vasodilatation and increased blood flow.

In addition to adenosine receptors, your vascular endothelial cells also have receptors for various other molecules (e.g. acetylcholine, bradykinin, substance P). These so-called ‘vasoactive’ molecules all ultimately cause vasodilation through the stimulation of NOS and the formation of nitric oxide (NO).

Overall then, there are two main triggers of NO release by vascular endothelial cells:

  • Increased blood flow through a blood vessel
  • Other ‘vasoactive’ molecules binding to receptors


  • Increases in blood flow during exercise stimulates vascular endothelial cells to produce more NO.
  • Other molecules (e.g. adenosine, bradykinin, acetylcholine) can also bind to vascular endothelial cells and stimulate them to produce more NO.

How does NO cause vasodilatation?

We’ve seen how NO is produced by vascular endothelial cells in the inner lining of your blood vessels. But how exactly does this lead to widening of blood vessels? To answer this, we need to look at the middle layer of the blood vessel walls. Found in this layer are rings of smooth muscle, called vascular smooth muscle. You’ll learn about this muscle type in greater detail in a later blog.

Once formed by NOS in your endothelial cells, nitric oxide (NO) diffuses into your vascular smooth muscle cells. Here it stimulates an enzyme called guanlyl cyclase, which produces a molecule called cGMP (cyclic guanosine monophosphate). Through various mechanisms (involving calcium ions, potassium ions and other enzymes), cGMP causes the rings of vascular smooth muscle to relax. When these rings relax, they dilate and the lumen of the blood vessel becomes wider. This allows more blood to flow through.

Interestingly, drugs which inhibit the breakdown of cGMP lead to greater vasodilatation. A good example of this is Viagra, which is used to treat erectile dysfunction by promoting blood flow to erectile tissue in the penis.


  • Nitric oxide diffuses from vascular endothelial cells in the inner lining to vascular smooth muscle in the middle layer of blood vessel walls.
  • Nitric oxide causes relaxation of vascular smooth muscle.
  • Relaxation of vascular smooth muscle allows blood vessels to widen and allows greater blood flow.

Other effects of nitric oxide (NO)

Nitric oxide doesn’t just cause vasodilatation. It also helps to prevent blood clots and reduce inflammation.

If you’ve ever cut yourself shaving, you’ll find that the bleeding quickly stops and a blood clot forms. This is largely due to one particular constituent of the blood: platelets. Platelets are essentially small plate-shaped cells which help to plug damage to blood vessels. They do this by first adhering to sites of injury to the inner lining of the blood vessels (i.e. the endothelium) and then binding to other platelets to form a clot.

This is obviously useful for stopping bleeding (e.g. after you’ve cut yourself shaving). In some circumstances, however, clots (called thrombi) can form in blood vessels and arteries and start to block them. This may interrupt blood flow to important organs and tissues. Nitric oxide (NO) can help to prevent this by stopping platelets from adhering to the vascular endothelium.

Similarly, nitric oxide also inhibits white blood cells from adhering to the blood vessel wall, which occurs during inflammation.


  • Nitric oxide prevents platelets from adhering to blood vessel walls.
  • Nitric oxide helps to prevent blood clots from forming inside blood vessels.
  • Nitric oxide can help to prevent inflammation within blood vessel walls.

Genetics of Nitric Oxide production

As with virtually all traits, both genes and environmental factors (e.g. diet, lifestyle) play a role in the production and function of nitric oxide (NO).


With regards to genes, variations (or SNPs – pronounced ‘snips’) in the NOS3 gene, which encodes the cNOS / NOS III (nitric oxide synthase) enzyme, may influence how well you make nitric oxide. For example, some variants of the NOS3 gene cause lower activity of the NOS enzyme, which may lead to lower levels of nitric oxide.

By contrast, other variants of the NOS3 gene may give rise to higher activity of the NOS III enzyme. This will lead to greater NO production, and possibly improved blood flow to exercising muscles.

Genes involved in BH4 production

As explained earlier, the NOS III enzyme requires other molecules (called ‘cofactors’) to function efficiently. One of these is BH4 (tetrahydrobiopterin). Variation in genes involved in the production and processing of BH4 can therefore influence how well your NOS III enzyme produces nitric oxide. An example of one of these genes is the GCH1 gene.

Other genes

As the human body is complex, the biological pathways associated with nitric oxide production are also intertwined with pathways regulating other processes: such as metabolism of folate, control of calcium levels, inflammation etc. As a result of this, genes involved these processes (e.g. the MTFHR, MTRR and MTR in folate metabolism) will influence nitric oxide production.

How can I increase my NO levels?

Depending on your FitnessGenes trait results, you may want to improve your body’s production of nitric oxide (NO). In turn, this may improve blood flow to muscles during exercise. There are several different ways to do this, including:

  • Increase your intake of nitrate rich foods

Nitric oxide can also be formed without the NOS enzyme, from nitrates in food. Consequently, one strategy to increase your nitric oxide levels is to eat foods rich in nitrate, such as beets, celery, lettuce, radishes, and spinach.

  • Supplement with L-arginine

As established, your vascular endothelial cells use the NOS III enzyme to produce NO from the amino acid, L-arginine. Your body can normally make enough L-arginine itself. Depending on your gene results, however, you may benefit from taking an L-arginine supplement to enhance your production of NO.

  • Supplement with L-citrulline

One product of NO formation is the amino acid L-citrulline. As stated previously, L-citrulline can be converted back into L-arginine, which can the be used to make more NO. Based on this pathway, L-citrulline supplements may be used to help indirectly boost levels of NO.

  • Consume a diet rich in plenty of antioxidants

Antioxidants such as Vitamin C, E and glutathione can help to reduce the breakdown of nitric oxide.

Dr Haran Sivapalan

A qualified doctor having attained full GMC registration in 2013, Haran also holds a first-class degree in Experimental Psychology (MA (Cantab)) from the University of Cambridge and an MSc in the philosophy of cognitive science from the University of Edinburgh. Haran is a keen runner and has successfully completed a sub-3-hour marathon during his time at FitnessGenes.

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