Endothelial Dysfunction

About the author

Dr. Yvo Sijpkens is an internist at Haaglanden Medical Center in The Hague and medical advisor to Stichting Je Leefstijl Als Medicijn. He specializes in lifestyle medicine and its application in conditions such as diabetes and metabolic dysfunction.

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In brief

• The endothelium is the inner lining of all blood vessels and regulates vasodilation, clotting and inflammation
• With endothelial dysfunction, vessels become stiffer, narrowed and inflammation-sensitive
• The glycocalyx and nitric oxide (NO) play a central role in vascular health
• Causes include hyperglycemia, obesity, smoking, hypertension and inactivity
• Lifestyle is an important target for recovery of endothelium and vascular function

1. What is the endothelium?

The endothelium is the single-cell layer on the inside of all blood vessels (arteries, veins, capillaries). It is an active organ that among other things:

• Regulates the diameter of blood vessels (dilation and constriction)
• Balances clotting and anticoagulation
• Directs inflammatory responses
• Regulates the exchange of oxygen, nutrients and waste products

A healthy endothelium keeps vessels supple, responsive and relatively inflammation-free.

2. What is endothelial dysfunction?

With endothelial dysfunction, this inner lining no longer works properly. Characteristic are:

• Blood vessels can dilate less well
• More inflammation and oxidative stress occur in the vessel wall
• The vessel wall becomes leaky and susceptible to LDL, immune cells and calcium
• The clotting system shifts toward more tendency to clot formation

Result: the vessels become stiffer, remain relatively narrowed and lose their adaptive capacity. This plays a central role in hypertension, atherosclerosis and organ damage.

3. Glycocalyx and nitric oxide (NO)

On the endothelium lies a gel-like protective layer: the glycocalyx. This works as a kind of teflon layer where blood cells and proteins glide along. The glycocalyx protects endothelial cells against mechanical and chemical damage and plays a role in the production of nitric oxide (NO).

Nitric oxide (NO) is a gaseous signaling molecule that:

• Relaxes smooth muscle cells in the vessel wall (vasodilation)
• Helps normalize blood pressure
• Inhibits platelet aggregation and inflammation

With endothelial dysfunction

With endothelial dysfunction, we often see damage or thinning of the glycocalyx and reduced activity of the enzyme eNOS (endothelial NO synthase). Therefore there is less NO, more oxidative stress and more vascular stiffness.

4. Main causes of endothelial dysfunction

4.1 Metabolic causes

1. Chronic hyperglycemia and insulin resistance

Repeated and prolonged glucose peaks lead to formation of AGEs (advanced glycation end products) that damage proteins in glycocalyx and endothelium. Insulin resistance disrupts the normal, vasodilating influence of insulin, resulting in less NO and more inflammation.

2. Metabolic syndrome and obesity (visceral fat)

Elevated free fatty acids, low-grade inflammation and hormonal disruptions activate the endothelium. This often goes together with hypertension, dyslipidemia and sleep apnea.

3. Dyslipidemia, especially an atherogenic lipid profile

A combination of high triglycerides, low HDL and many small, dense LDL particles promotes oxidation and uptake of these particles in the vessel wall.

4. Fructose excess, especially in liquid form

Excessive intake of soft drinks, fruit juices and other sweetened drinks increases among other things uric acid and promotes oxidative stress in endothelial cells.

4.2 Diet and gut health

5. Ultra-processed food and unstable fats

The combination of refined carbohydrates, industrially processed oils, additives and much salt promotes obesity, hyperglycemia and inflammation.

6. Disrupted gut barrier and endotoxins

Increased passage of bacterial components (such as LPS) into the bloodstream can cause systemic low-grade inflammation.

4.3 Classic cardiovascular risk factors

7. Smoking

Smoking gives a strong increase in oxidative stress, direct endothelial damage and increased clotting tendency.

8. Hypertension

High blood pressure gives mechanical stress on the vessel wall that damages endothelium and glycocalyx. This creates a vicious cycle.

9. Chronic kidney disease

Uremic toxins, disturbances in calcium-phosphate balance and chronic inflammation damage the vessel wall.

10. Chronic inflammatory and autoimmune diseases

Rheumatoid arthritis, SLE, psoriasis and other systemic inflammatory conditions accelerate endothelial dysfunction and atherosclerosis.

4.4 Lifestyle and environment

11. Inactivity and low VO2max

Little physical exertion means less favorable shear stress from blood flow on the endothelium, less eNOS activation and poorer mitochondrial function.

12. Sleep deprivation and sleep apnea

Intermittent hypoxia, sympathetic activation and elevated cortisol damage the endothelium and raise blood pressure.

13. Chronic psychosocial stress

Prolonged elevated cortisol, adrenaline and noradrenaline promote vasoconstriction, higher blood pressure and oxidative stress.

14. Air pollution

Fine particles and nitrogen oxides from traffic and industry are associated with endothelial dysfunction and cardiovascular events.

5. Consequences of endothelial dysfunction

Endothelial dysfunction is early in the chain of various disease conditions:

• Hypertension and increased arterial stiffness
• Atherosclerosis (coronary artery disease, TIA or stroke, peripheral arterial disease)
• Heart failure, especially HFpEF
• Microvascular angina (ischemic symptoms with apparently normal coronary arteries)
• Chronic kidney damage
• Erectile dysfunction (often an early marker of systemic endothelial problems)
• Diabetic microangiopathy (retinopathy, nephropathy, neuropathy)

6. Diagnostics (indirect)

In routine care, endothelial or glycocalyx function is rarely measured directly. Indirect estimation can be via:

Method	Examples
Clinical risk factors	Smoking, diabetes, hypertension, dyslipidemia, obesity, sedentary lifestyle
Laboratory testing	Fasting glucose, HbA1c, triglycerides/HDL ratio, kidney function, hs-CRP
Specialist measurements	Flow mediated dilation, pulse wave velocity

7. Medical treatment

The goal is treating underlying risk factors and relieving the vessel wall.

1. Blood pressure lowering medication

ACE inhibitors and ARBs have both blood pressure lowering and endothelial protective effects.

2. Lipid lowering therapy

Statins, possibly supplemented with ezetimibe or PCSK9 inhibitors, lower LDL cholesterol and have pleiotropic effects on inflammation and endothelium.

3. Glucose lowering medication

Metformin, SGLT2 inhibitors and GLP-1 agonists improve glycemia and weight and have favorable effects on blood pressure and cardiovascular outcomes.

4. Antithrombotic therapy

For manifest atherosclerosis or high cardiovascular risk, platelet inhibitors are applied according to guidelines.

Combination

Medication does not replace lifestyle treatment, but ideally works together with intensive lifestyle approach.

8. Lifestyle and dietary interventions

Lifestyle is an important target for recovery of endothelium and vascular function.

8.1 Diet

Goals are: stabilizing glucose, reducing low-grade inflammation and supporting glycocalyx and endothelium.

• Carbohydrate restriction or low-carb, possibly ketogenic, preferably with expert guidance
• Limiting fast sugars and fructose, especially in liquid form
• Less ultra-processed food - choose unprocessed products
• Careful with unstable fats - avoid repeated heating and frying
• Sufficient protein supports recovery and muscle mass
• Vegetables with nitrates (beets, arugula, celery) can contribute to NO production
• Limit alcohol, especially with hypertension or fatty liver

8.2 Exercise and VO2max

• 150 to 300 minutes of moderate intensity exercise per week
• 2 to 3 times per week strength training
• Interval training (HIIT) can raise VO2max and stimulate eNOS activation
• Much daily movement provides favorable shear stress

8.3 Sleep

• 7 to 9 hours of quality sleep per night
• Screen for obstructive sleep apnea if indicated
• Fixed bed and wake times, dark and cool bedroom

8.4 Stress, vagus nerve and recovery

• Breathing exercises, meditation, relaxation techniques
• Exercise, nature and social support
• Activation of the vagus nerve contributes to lower blood pressure and less inflammation

8.5 Stopping smoking

Stopping smoking is one of the most powerful measures to improve endothelium and vascular function.

9. Practical step-by-step plan

Step 1 - Measure and map risk

Have blood pressure, weight, waist circumference, fasting glucose, HbA1c, lipid profile and kidney function determined.

Step 2 - Reset diet (at least three months)

Eliminate liquid sugars and highly processed snacks. Shift to a carbohydrate-restricted pattern with unprocessed products.

Step 3 - Daily movement and training

Minimum 30 minutes of walking per day. Add 2-3 times per week strength training and 1-2 times per week interval form.

Step 4 - Sleep and stress

Optimize sleep hygiene and plan a short relaxation routine daily.

Step 5 - Smoking and alcohol

Stop smoking. Limit or stop alcohol use.

Step 6 - Evaluation

Evaluate after 3 to 6 months blood pressure, weight, metabolic parameters and symptoms.

10. When to contact a doctor?

Contact urgently for

• Blood pressure values around or above 180/110 mmHg
• Symptoms of chest pressure, shortness of breath at rest
• Neurological deficit (drooping face, speech problems, paralysis)

Contact easily for

• New or increasing exertion-related chest pain
• Claudication symptoms (leg pain when walking)
• TIA-like symptoms
• Rapid weight gain, nocturnal shortness of breath or ankle edema
• Deterioration with existing diabetes or known vascular disease

Veelgestelde vragen

What is the endothelium?

The endothelium is the single-cell layer on the inside of all blood vessels. It regulates blood vessel diameter, balances clotting, directs inflammatory responses and regulates the exchange of oxygen and nutrients. A healthy endothelium keeps vessels supple and inflammation-free.

What is endothelial dysfunction?

With endothelial dysfunction, the vessel lining no longer works properly. Blood vessels can dilate less well, more inflammation and oxidative stress occur, and the clotting system shifts toward more clot formation. This plays a central role in hypertension and atherosclerosis.

What is the glycocalyx?

The glycocalyx is a gel-like protective layer on the endothelium that works like a teflon layer where blood cells glide along. With endothelial dysfunction, this layer becomes damaged or thinned, leading to less nitric oxide (NO), more oxidative stress and more vascular stiffness.

How can I improve endothelial dysfunction?

Through carbohydrate restriction, stopping smoking, 150-300 minutes of exercise per week with strength training, 7-9 hours of sleep, stress reduction and limiting alcohol. Medication such as ACE inhibitors, statins and metformin can additionally help.

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