Peripheral artery disease (PAD) in the legs is caused by a gradual narrowing of the arteries that supply blood to your lower limbs. The underlying process is usually atherosclerosis, a buildup of fatty deposits inside artery walls that restricts blood flow. Over 90% of the disease burden falls on people aged 70 and older, but the arterial damage that leads to PAD begins decades earlier, driven by a combination of modifiable risk factors and genetic predisposition.
How Arteries Become Narrowed
Healthy arteries have a smooth inner lining that produces nitric oxide, a molecule that keeps blood vessels relaxed and open. When that lining becomes damaged, it loses the ability to produce enough nitric oxide, and the artery walls stiffen. This damage sets off a chain reaction: immune cells stick to the injured lining, slip beneath it, and begin absorbing cholesterol. Over time, these fat-laden immune cells form plaques that bulge inward, reducing the space available for blood to flow through.
PAD in the legs has some distinct features compared to artery disease in the heart. In coronary artery disease, blockages are usually caused by plaques that rupture or erode and trigger clots. In leg arteries, roughly two-thirds of severe blockages involve clot formation even without significant plaque buildup, suggesting that the inner lining of leg arteries is especially vulnerable to dysfunction on its own. This means that even before large plaques develop, the arteries feeding your calves and feet can begin to close off.
The Role of Chronic Inflammation
Inflammation is not just a side effect of PAD. It actively drives the disease forward. When artery walls are damaged, the body releases signaling proteins that attract white blood cells to the site. These cells burrow into the artery wall, release more inflammatory signals, and recruit still more immune cells. The cycle feeds on itself.
One key marker of this process is C-reactive protein (CRP), a substance the liver produces in response to inflammation. In a study of 387 PAD patients, those with the highest CRP levels had significantly worse blood flow to their legs than those with the lowest levels. Higher CRP doesn’t just reflect existing damage; lab studies show it actively attracts immune cells to artery walls, promotes clotting, and suppresses nitric oxide production. Other inflammatory signals, including molecules that act like cellular glue (holding immune cells against the artery lining), are consistently elevated in people with PAD and correlate with disease severity.
Smoking Is the Strongest Modifiable Risk
Smoking damages artery linings directly, accelerates plaque formation, and makes blood more likely to clot. People who have smoked heavily (more than 40 pack-years, roughly a pack a day for 40 years) are four times more likely to develop PAD than nonsmokers. Even lighter smoking over a long period raises risk substantially. Smoking also worsens symptoms in people who already have PAD, making it harder to walk without pain and increasing the chance of severe complications.
The damage from smoking is partly reversible. Quitting slows plaque progression and improves artery function over time, though the benefit depends on how much damage has already accumulated.
Diabetes and Blood Sugar Damage
Diabetes is one of the most potent drivers of PAD, and it makes the disease harder to treat once it develops. Chronically elevated blood sugar damages artery linings in several ways: it increases oxidative stress (a form of chemical damage to cells), impairs nitric oxide production, and creates a persistent low-grade inflammatory state throughout the body.
Perhaps most importantly, diabetes interferes with your body’s ability to grow new blood vessels around a blockage. When an artery narrows, the body normally sprouts small detour vessels to reroute blood flow. Diabetes disrupts the growth signals that guide this process, leaving tissues downstream of a blockage with fewer rescue options. This is a major reason why people with diabetes who develop PAD face a much higher risk of severe outcomes, including tissue death and amputation. An ankle-brachial index (a simple blood pressure comparison between the ankle and arm) of 0.90 or below confirms PAD, and in people with diabetes, that reading carries an eightfold increase in seven-year amputation risk.
High Blood Pressure and Cholesterol
High blood pressure forces blood against artery walls with excess force, gradually damaging the inner lining and making it easier for cholesterol to penetrate. Over years, this mechanical stress contributes to the stiffening and thickening of artery walls throughout the body, including the legs.
High cholesterol feeds the process more directly. The cholesterol particles that accumulate inside artery walls are primarily LDL (“bad” cholesterol). Once LDL crosses into the artery lining, it becomes chemically modified and triggers the immune response that builds plaques. Controlling both blood pressure and cholesterol slows this cascade considerably.
Age and Genetics
Age is the single strongest predictor of PAD. The disease is rare before 70: fewer than 10% of global PAD cases, deaths, and disability occur in people under that age. After 70, risk climbs sharply. This reflects decades of cumulative arterial wear, compounded by the natural decline in the body’s repair mechanisms.
Genetics also play a role independent of lifestyle. A family history of PAD, heart disease, stroke, or other blood vessel conditions raises your risk. Researchers have identified specific gene variations linked to PAD, including one involved in factor V Leiden, a clotting disorder that makes blood more prone to forming clots inside arteries. Other gene variants appear to increase susceptibility to atherosclerosis across multiple vascular beds, meaning the same genetic hand that raises heart attack risk can also raise PAD risk.
How These Factors Work Together
PAD rarely has a single cause. In most people, it results from several risk factors compounding over time. A person who smokes and has high blood pressure, for instance, is damaging their arteries through two separate mechanisms simultaneously: chemical toxins from tobacco and physical force from elevated pressure. Add diabetes or high cholesterol, and the artery lining faces assault from multiple directions at once.
This is also why PAD in the legs often signals broader vascular disease. The same processes narrowing your leg arteries are likely affecting arteries elsewhere, including those supplying the heart and brain. Managing the underlying causes, particularly quitting smoking, controlling blood sugar, and lowering cholesterol and blood pressure, addresses PAD and reduces the risk of heart attack and stroke at the same time.
Early Warning Signs to Recognize
The most common early symptom is cramping or aching in your calves, thighs, or hips during walking that goes away within a few minutes of rest. This pattern, called intermittent claudication, happens because narrowed arteries can’t deliver enough blood to meet your muscles’ demand during exercise. Some people notice their feet feel cold, or that one leg is noticeably cooler than the other. Wounds on the feet or toes that heal unusually slowly are another signal.
Many people with PAD have no symptoms at all in the early stages, which is part of what makes the risk factors above so important to manage. By the time symptoms appear, the arteries may already be significantly narrowed. A simple test comparing blood pressure at the ankle to blood pressure at the arm can detect PAD before symptoms develop, and values at or below 0.90 confirm the diagnosis. Values between 0.91 and 1.00 are considered borderline and worth monitoring.