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Endothelial Dysfunction: A Common Factor in Diabetes, Atherosclerosis, and Hypertension

Stroke Risk, Prevention, and the Atherosclerosis Connection

As a result of a reciprocal relationship, three widespread health conditions - diabetes, atherosclerosis, and hypertension all affect (and are affected by) a layer of cells that line our blood vessels called the endothelium. Addressing issues with the endothelium can help reduce the seriousness of these three health conditions and, in some cases, help prevent the conditions from forming. Likewise, managing or preventing diabetes, atherosclerosis, and hypertension can spare damage to blood vessels all over the body.

A large part of human suffering in the US is created by cardiometabolic diseases - diabetes, atherosclerosis, and hypertension, all of which can be a cause and an effect of damaged endothelium. By CDC estimates, an astounding 37 million Americans have diabetes, including about 8 million who have diabetes and don't know it (1). Atherosclerosis (the buildup of plaques in the arteries around the heart), also called "Coronary Artery Disease," affects about 18 million American adults (2). In 2020, over 670,000 deaths in the US were either primarily caused by hypertension or hypertension was a contributing factor (3). These statistics are sobering.

However, there is excellent news. Diagnosing and addressing endothelium issues has a massive, widespread positive impact on health. Not only does the treatment of endothelial problems reduce risks for severe illnesses, but it can also address the symptoms of concurrent diseases such as diabetes, atherosclerosis, and hypertension. Endothelial tissue treatments can stop feedback loops that result in a spiral of ever-decreasing health. Indeed, many of the treatments for diabetes, atherosclerosis, and hypertension aim to prevent or repair damage to the endothelium. This article examines the endothelium, how disruptions are diagnosed, and how it can be treated.

60,000 Miles of Endothelium in the Human Body?

The endothelium is a single layer of cells lining the inside surface of blood vessels in the vascular system, such as arteries, veins, and capillaries. Chemicals, toxins, stress, and medications can chemically interact with endothelium. The vascular endothelium (as opposed to the endothelium that lines the lymphatic system) has a lengthy list of functions, as it (4-6):

  • Lines about 60,000 miles of blood vessels in the human body

  • Helps blood reach all areas of the body

  • Controls the relaxation and contraction of blood vessels, allowing greater or lesser volumes of fluid to flow through the circulatory system

  • Forms "vascular tone" by affecting the contraction and relaxation of the vessels

  • Secretes growth promoters and inhibitors, affecting the growth of vessels

  • Regulates the movement of substances from the bloodstream into the tissues surrounding the vessels, relaxing when healing substances need to pass, but tightening to prevent toxic substances from passing into tissues

  • Produces nitric oxide (NO) and prostacyclin, which relax the vessels and help prevent blood clotting

  • Regulates coagulation of blood

  • Provides a space between human tissues and the blood where many significant interactions occur

  • Inflames as a result of remote factors, or produces inflammatory substances, such as Reactive Oxygen Species (ROS)

Nitric Oxide (NO) deserves special mention. Created by the endothelium, nitric oxide helps keep arteries open. Reduced NO can result in narrower blood vessels, which causes high blood pressure (hypertension). NO also fights inflammation, so if there is too little NO, inflammation in the artery walls can increase. Lack of NO can also increase the production of platelets, which are the elements in the blood that help create clots. Lastly, a lack of adequate NO can increase the porousness of blood vessel walls, allowing damaging substances through to nearby tissues (7).

It's evident that healthy endothelium and its tight control over NO is vital to many body functions. What happens when it goes awry?

Endothelial Dysfunction: When Artery Linings Fail

The endothelium performs delicate steps of accommodation, attempting to balance the relaxing, contracting, and inflammatory forces within the vessels it inhabits. Any strong disturbance of this sensitive mechanism can be called "endothelium dysfunction." Because vascular endothelium lines the blood vessels in so much of the body, imbalances tend to have widespread negative consequences, such as contributing to chronic health issues including atherosclerosis, diabetes, obesity, dyslipidemia (disordered cholesterol), and hypertension (8).

The details of how to classify different types of endothelial dysfunction are still being worked out, though one scientific review highlights three possible classifications (9). One classification is a distinction between acquired versus genetic. Risk factors can be passed down through family lines genetically. Or, endothelial dysfunction can be secondary to having some other disease (such as diabetes, hypertension, or atherosclerosis.) In secondary dysfunction, typically, the endothelium loses the ability to create nitric oxide (NO), which narrows blood vessels while at the same time increasing proinflammatory and pro-clotting factors.

Another classification centers on how much nitric oxide (NO) is produced in the endothelium. Lack of NO increases the risk of spasms and blood vessel blockage by a blood clot (called thrombosis). This mechanism ties into the dangers associated with diabetes, hypertension, dyslipidemia, atherosclerosis, and other health conditions. Too much NO, sometimes initiated by heart bypass surgery or sepsis, cascades into activating the immune system, creating free radicals, and releasing factors that increase clotting.

Symptoms of Endothelial Dysfunction:

Unfortunately, many people feel no discernible symptoms even though they may have advanced endothelial dysfunction. By the time symptoms occur, there may be significant damage to the linings of the blood vessels and even the organs that exist beyond. If there is a symptom, it tends to be angina (chest pain) that worsens when physically active (7).

Endothelial Dysfunction Risk Factors:

Endothelial dysfunction can be secondary to having another health condition. In other words, having one of the following health conditions can cause endothelial dysfunction (10):

  • High cholesterol (dyslipidemia)

  • High blood pressure (hypertension)

  • Obesity

  • Metabolic syndrome (a collection of occurrences: high blood pressure, high triglycerides, low HDL, enlarged waist, insulin resistance)

  • Autoimmune diseases (where the immune system mistakenly attacks itself)

  • Smoking

Smoking deserves special mention when discussing risk factors. Smoking creates oxidative stress, an imbalance between free radicals (which can steal oxygen atoms) and antioxidants (which donate oxygen atoms). Oxidative stress has many health consequences, including cardiovascular diseases, neurodegenerative diseases, cancer, kidney disease, muscle loss associated with aging (sarcopenia), and overall frailty (11). Smoking plays a significant role in disrupting the endothelium layer and can set off a chain of events that eventually cause the lining to fail as a functional barrier (12).

The Relationship of Endothelium Dysfunction to Atherosclerosis and Arteriosclerosis

Arteriosclerosis is a broad category that includes any hardening or thickening of the arteries. This stiffness can restrict blood flow due to its inflexibility and can be a natural result of aging, where the elasticity of the artery walls is lost.

Atherosclerosis is a subtype of arteriosclerosis, denoting that the stiffness comes from plaque buildup (rather than hardening from aging or something else) (14).

Current science shows that the buildup of plaque in the large arteries around the heart, called atherosclerosis, begins its process as disrupted or dysfunctional endothelium (13). Once the lining of the artery gets disrupted, the texture changes, making it easier for items in the blood to adhere to that area. As platelets, white blood cells, and cholesterol (especially small, dense LDL) pass by the disrupted endothelium, they stick to the rough patch, forming a plaque.

The plaque begins blocking more of the blood flow as it grows. The growth of plaques can contribute to the stiffness of the arteries because plaques prevent the artery from stretching properly in response to pressure. The circulation system is usually a closed system, branching out from and returning to the heart. When the heart beats, the blood rushes forth under pressure (the "systolic"), and the arteries expand a little under the force of this pressure. If the arteries are stiff, they do not expand, which causes the pressure within to be higher.

This highlights the importance of nitric oxide produced by the endothelium- it helps the vessel to relax and expand under the pressure of the heartbeat.

Diagnosis of Endothelium Dysfunction:

Cardiologists may use CT scans, MRIs, electrocardiograms, and many other technologies to diagnose artery disorders, including endothelial dysfunction. However, the Primary Care Physician often finds the first clue that a patient has vascular or arterial issues. Hints of endothelial dysfunction may come in many forms:

  • Blood tests showing inflammation markers (ex: homocysteine, c-reactive protein)

  • Blood pressure measurements

  • Diagnoses of conditions that present risks (hypertension, diabetes, tobacco use)

  • Blood oxygen saturation level as measured by pulse-oximeter

  • Diagnosis of atherosclerosis, which typically begins as prolonged endothelium dysfunction (13)

  • Plethysmography testing (see below)

Plethysmography Testing to Detect and Diagnose Artery Issues

At the Temecula Center for Integrative Medicine (TCIM), plethysmography testing may be added to the round of tests performed during an executive physical based on an individual’s risk factors. Plethysmography uses arterial pulse wave measurements to detect issues with the arteries that could have endothelium dysfunction at their core, such as hardening of the arteries or a restriction of blood circulation. A plethysmography device detects tiny changes in blood flow within the body.

There are many different types of devices, and TCIM uses a "fingertip photoplethysmogram," which utilizes a simple finger clamp similar to the pulse oximeter. Through the finger clamp, infrared light is passed through the skin, and advanced software interprets the returning signals (15). This simple plethysmography test can be performed in the office in minutes with little preparation. Despite its simplicity, the report from this device is compelling, giving practical, actionable information about (16):

  • Heart rate (heartbeats per minute)

  • HRV- heart rate variability (the amount of time between heartbeats, where a higher variability indicates greater health)

  • The shape of the arterial pulse wave (estimates the condition of the arteries from healthy to poor and gives a percentage of arteries that fall into each category)

  • Artery elasticity (deficient elasticity indicates a high level of stiffness of large arteries and may point to the need for additional testing through a cardiologist)

  • Peripheral elasticity (estimates stiffness of smaller arteries away from the core of the body)

  • An estimate of autonomic nervous system activity (detects if a patient is stuck in "fight or flight" mode with high activation of the sympathetic nervous system)

  • Ectopic beats (a premature beat of the heart that feels like it "skipped" a beat)

The results from the plethysmography testing are interpreted by our doctors, who use the information to assess risks for heart attack and stroke and suggest other types of testing.

The best thing about this type of testing is the potential to pick up on cardiovascular issues long before any symptom is felt. Early detection gives patients more time to address the issue before a severe consequence is experienced.

Prevention of Endothelium Dysfunction

Many suggestions for preventing endothelium dysfunction are general and familiar. Studies continue to discover beneficial foods that reduce inflammation in the arteries or strengthen the tissues of the artery walls. Any foods, nutritional supplements, medications, or physical activity that reduce inflammation, increase the availability of nitric oxide, or improve flexibility of the artery wall will significantly reduce the risk of disrupted artery linings and plaque formation. Our recommendations include the following:

1) Schedule regular doctor visits. Annual checkups are your best bet for early detection and treatment of conditions that can cause endothelium dysfunction.

2) Quit smoking. Smoking increases free radicals, decreases oxygen intake, and brings toxins into the system, all of which are damaging to arteries. Our team is available to support and assist you through the process.

3) Exercise or do breathing exercises to increase the overall intake of oxygen, address hypertension, and reduce stress. Deep breathing helps more oxygen reach more cells. Healthy cells can use oxygen to repair themselves and repair tissues.

4) High-intensity interval training (HIIT), which involves alternating high effort followed by low effort in cycles, helps condition the heart by increasing heart rate variability (HRV) (17). Conditioning the heart means that the heart muscle gets a workout, and the arteries get practice expanding and contracting, making them more flexible.

5) Eat a whole foods diet high in antioxidants, nitric oxide contributors, and natural blood thinners such as beets, chlorella (18), and polyphenols (apples, turmeric, green tea, grapes) (19, 20).

6) Supplement with antioxidants, nitric oxide contributors, polyphenols, and natural blood thinners. Supplement form allows a concentration of healthy nutrients. CoQ10, vitamin C, beet powder, green tea extracts, and resveratrol are all great choices. Turmeric (and its extract curcumin) is naturally blood-thinning, as are Boswellia, Omega-3 fatty acids, and nattokinase. Check with your doctor before taking blood-thinning supplements if you are on prescription blood thinners, as the combination could be dangerous.

7) Change your cooking oils. A particularly damaging disruptor to the arterial endothelium is cooking oils that have gone over their "smoke point." Each oil has a temperature at which it breaks down, called its smoke point. If the oil exceeds its smoke point during cooking or during the processing of the oil (before it lands on the grocery store shelf), the oil becomes unstable and can cause free radicals to be made by nearby tissues.

  • Free radicals are so damaging that they rough up the artery lining (endothelium) surface, allowing a place for clots or plaques to form. Free radicals also play a role in oxidizing any cholesterol in the plaque (21), making it brittle and subject to breaking off. Plaques that break off migrate into smaller and smaller blood vessels until they get stuck and create a complete blockage, which increases the risk of stroke or heart attack. Antioxidants such as CoQ10 and vitamin C can help "quench" free radicals by donating electrons without being destabilized themselves.

  • Avocado and high-heat coconut oils have a very high smoke point and are relatively tasteless, making them acceptable for frying foods. Ensure you get cold-pressed, high-quality oils, as some brands have been diluted with vegetable oils. Vegetable oils made from corn, cottonseed, soybean, safflower, or canola have notoriously low smoke points and contribute to inflammation if used in frying. After they break down under heat, these vegetable oils create conditions ripe for growing plaques and producing inflammation. (Note that most restaurants and almost all fast-food restaurants use vegetable oils to fry in.)

Potential Endothelium Dysfunction Treatments

Severe cases of endothelium dysfunction will garner a referral to a cardiologist for further diagnosis and care. Even moderate results on plethysmography testing could be grounds for visiting a cardiologist, depending on patient history and results from blood tests that help form a complete picture of potential health outcomes. There are two basic approaches:

1) Treat the condition that led to endothelium dysfunction. If you have diabetes, hypertension, or any condition that can inflame or damage the arteries, treat that disease to manage it or eliminate it. This situation may require medication.

2) Treat endothelium dysfunction directly. All the prevention steps above can be used as treatments. Additionally, hyperbaric oxygen and ozone therapies can aid healing due to their ability to increase oxygen levels. Finding the source of the arterial disturbance is paramount to good treatment strategies.

In Conclusion

At TCIM, we understand that achieving vibrant health can take commitment and effort. During our executive physicals, our doctors provide excellent diagnostic skills using advanced testing techniques because spotting a health condition in the early stages can save you months and years of time and effort. Finding and addressing a health issue swiftly can mean adding decades to your lifespan and helping you feeling better than ever. Even if you have ignored your health for a long time and have almost given up hope of achieving a healthy state, let us help you. Don't give up hope. We will partner with you and provide support and customized treatments for your situation.


Jonathan Vellinga, M.D.

Jonathan Vellinga, MD is an Internal Medicine practitioner with a broad interest in medicine. He graduated Summa cum laude from Weber State University in Clinical Laboratory Sciences and completed his medical degree from the Medical College of Wisconsin.​

Upon graduation from medical school, he completed his Internal Medicine residency at the University of Michigan. Dr. Vellinga is board-certified with the American Board of Internal Medicine and a member of the Institute for Functional Medicine.




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