Arteriosclerosis is caused by a combination of forces that damage and stiffen your arteries over time, including high blood pressure, high cholesterol, smoking, diabetes, chronic inflammation, and the natural aging process. No single factor works alone. These causes layer on top of each other, and the more of them you have, the faster your arteries lose their flexibility and narrow.
Arteriosclerosis vs. Atherosclerosis
These two terms are often used interchangeably, but they describe different things. Arteriosclerosis is the broader term for any stiffening or hardening of artery walls. It’s a degenerative process that affects the middle layer of large elastic arteries, where the structural fibers that give arteries their stretch gradually break down, fragment, and get replaced by stiffer tissue. Think of it as the artery losing its ability to flex with each heartbeat.
Atherosclerosis is one specific type of arteriosclerosis. It involves the buildup of fatty plaques inside arteries, particularly in the coronary arteries feeding the heart, the carotid arteries in the neck, and the arteries supplying the legs. The two conditions often coexist but don’t always track together. Studies comparing them at autopsy have found only weak correlations, and they respond differently to standard risk factors beyond blood pressure and age. They may increase your risk of cardiovascular disease through separate but complementary mechanisms.
How Plaque Builds Up Inside Arteries
The process that leads to fatty plaque formation follows a predictable sequence, and it starts with damage to the inner lining of your arteries. This lining, called the endothelium, is a single layer of cells that normally acts as a gatekeeper, controlling what passes from the blood into the artery wall. When this lining is disrupted by high blood pressure, tobacco chemicals, high blood sugar, or turbulent blood flow at branch points, it stops functioning properly. The artery wall becomes prone to constriction, inflammation, and infiltration by cholesterol particles.
Once the lining is compromised, LDL cholesterol particles slip into the artery wall, where they become chemically modified through oxidation. These oxidized particles act as an alarm signal. White blood cells called monocytes stick to the damaged lining, squeeze through it, and transform into larger immune cells called macrophages. These macrophages aggressively consume the oxidized cholesterol, swelling into what pathologists call “foam cells” because of their bubbly, fat-filled appearance. A mass of these foam cells creates the first visible sign of disease: a fatty streak just beneath the artery’s inner surface.
Over years, this fatty streak grows. Smooth muscle cells migrate from deeper layers of the artery wall into the growing mass, and a fibrous cap forms over the top. Beneath that cap, foam cells die through various forms of programmed cell death, releasing their contents and forming a soft, unstable core. If the fibrous cap ruptures, the contents spill into the bloodstream and trigger a blood clot, which is the mechanism behind most heart attacks and many strokes.
High Blood Pressure
Chronically elevated blood pressure is one of the most potent drivers of arterial stiffening. Every time your heart beats, a pressure wave travels through your arteries, stretching them slightly. When that pressure is consistently too high, it triggers a remodeling process in the artery wall. Smooth muscle cells in the wall respond to the increased mechanical stress by shifting their behavior. They begin producing extra structural proteins, thickening the wall to absorb the load.
The middle layer of the artery thickens without adding new cells, while the outer layer thickens with an increase in cell density and infiltration of inflammatory cells. Over time, the elastic fibers that allow arteries to stretch and recoil become damaged and are replaced by stiffer collagen. The smooth muscle cells cycle through phases of increased contraction and structural remodeling before eventually settling into a stiffer, less responsive state. The result is an artery that resists blood flow rather than accommodating it, which in turn raises blood pressure further, creating a self-reinforcing cycle.
Cholesterol and Oxidized LDL
LDL cholesterol isn’t dangerous simply because it circulates in your blood. The problem begins when LDL particles penetrate the artery wall and become oxidized. Once modified, oxidized LDL triggers a chain of inflammatory events. It causes the artery lining to produce sticky molecules that attract white blood cells, pulling them out of the bloodstream and into the wall. Those white blood cells then differentiate into macrophages that gorge on the oxidized particles.
Normally, cells maintain a balance between taking in cholesterol and pumping it back out. In the environment of a developing plaque, that balance breaks. The receptors that pull cholesterol in are ramped up, while the transporters that move cholesterol out are suppressed. Macrophages become trapped, overloaded, and eventually die, dumping their inflammatory contents into the growing plaque. This triggers further immune activation, more cell recruitment, and ongoing tissue damage. The activated macrophages also release enzymes that degrade the structural proteins holding the plaque together, making it more likely to rupture.
Smoking and Tobacco Chemicals
Cigarette smoke contains thousands of chemicals, including reactive compounds that directly damage the artery lining. The core problem is that smoking cripples the artery’s ability to produce nitric oxide, a molecule that keeps arteries relaxed, prevents blood cells from sticking to the walls, and limits inflammation.
Exposure to cigarette smoke depletes a critical helper molecule that the nitric oxide-producing enzyme needs to function. Without it, the enzyme essentially malfunctions. Instead of producing protective nitric oxide, it generates damaging free radicals, a process researchers call “uncoupling.” The result is a double hit: less of the molecule that protects arteries and more of the molecules that damage them. This makes smoking one of the most direct chemical insults to arterial health.
Diabetes and High Blood Sugar
Persistently elevated blood sugar damages arteries through a process that is distinct from cholesterol-driven plaque formation. Glucose molecules in the blood react with proteins in artery walls, forming compounds called advanced glycation end products, or AGEs. This happens slowly and non-enzymatically, meaning it’s a passive chemical reaction that accelerates whenever blood sugar is high and accumulates in people with a long history of diabetes.
AGEs cause damage in two ways. First, they cross-link structural proteins like collagen and elastin, essentially gluing them into rigid formations that can no longer flex. This directly increases arterial stiffness, which is an independent predictor of future cardiovascular events in both healthy people and those already at high risk. Second, AGEs activate inflammatory pathways in the artery wall, compounding the damage from other causes. This is why people with poorly controlled diabetes develop cardiovascular complications at much higher rates and at younger ages.
Aging and Elastin Breakdown
Even without any other risk factors, arteries stiffen with age. The primary reason is the gradual loss of elastin, the protein that gives arteries their ability to stretch and snap back with each heartbeat. Elastin is produced mostly during development and early life. As you age, the body’s ability to synthesize new elastin declines, while existing elastin fibers accumulate decades of mechanical wear from billions of heartbeats.
The aging artery undergoes several simultaneous changes. Elastin fibers fragment and calcify. Collagen production becomes dysregulated, driven partly by increased signaling from growth factors, leading to fibrosis and further stiffening. AGEs accumulate even in people without diabetes, cross-linking the remaining structural proteins. The net effect is that large arteries gradually transform from elastic, compliant vessels into stiffer conduits. This forces the heart to work harder with each beat and exposes smaller downstream vessels to higher pulsatile pressure.
Genetic Factors
Some people carry genetic risk for arteriosclerosis that exists independently of lifestyle. The clearest example is lipoprotein(a), often written as Lp(a), a cholesterol-carrying particle whose blood levels are more than 90% determined by genetics. Unlike standard LDL cholesterol, Lp(a) levels are largely set at birth and don’t respond much to diet or exercise.
Lp(a) is now recognized as an independent causal driver of atherosclerotic cardiovascular disease, not just a marker of residual risk. It promotes artery damage through distinct pro-inflammatory, pro-clotting, and pro-calcification pathways, meaning it attacks arteries from multiple angles simultaneously. Because Lp(a) is so heavily influenced by a single gene locus on chromosome 6, it can cause significant cardiovascular risk even in people who appear otherwise healthy. Standard cholesterol tests don’t measure it, so many people with elevated Lp(a) don’t know they have it.
Diet and Inflammatory Triggers
What you eat influences arteriosclerosis primarily through its effects on blood lipids and systemic inflammation. Trans fats, the industrially produced fats found in some processed foods, are among the most clearly harmful dietary factors. A 16-week randomized trial in women found that consuming industrially produced trans fats increased levels of tumor necrosis factor alpha, a key inflammatory signaling molecule, by 12% compared to controls. Receptors for this inflammatory molecule were also significantly elevated. Cross-sectional studies have linked trans fat intake to higher levels of multiple inflammatory markers associated with cardiovascular disease.
The mechanism appears to involve activation of the body’s inflammatory signaling systems in ways that promote the same endothelial damage, immune cell recruitment, and plaque instability seen in the disease process. While many countries have restricted or banned industrially produced trans fats, they still appear in some food supplies and remain relevant to understanding what drives arterial disease at a population level.
Where Arteriosclerosis Causes Problems
The consequences of stiffened, narrowed arteries depend on which arteries are affected. In the coronary arteries, reduced blood flow causes chest pain during exertion, and plaque rupture causes heart attacks. In the carotid arteries, the same process leads to strokes. In the legs, peripheral artery disease causes pain during walking, poor wound healing, increased infection risk, and in severe cases, amputation.
One complication that is increasingly recognized is kidney damage. Data from the Atherosclerosis Risk in Communities study found that people with symptomatic peripheral artery disease had more than double the risk of developing end-stage kidney disease compared to those without it. Even people with peripheral artery disease who had no symptoms carried a 75% increased risk. The study also found elevated rates of chronic kidney disease in both groups, suggesting that kidney complications from arterial disease are significantly underrecognized.
Measuring Inflammation Risk
Because inflammation plays such a central role in arteriosclerosis, a blood test for high-sensitivity C-reactive protein (hs-CRP) can help gauge your level of arterial inflammation. The risk categories are straightforward: below 1.0 mg/L is considered low risk, 1.0 to 3.0 mg/L is intermediate risk, and above 3.0 mg/L is high risk for future cardiovascular events. For people already diagnosed with cardiovascular disease and taking cholesterol-lowering medication, a level of 2.0 mg/L or higher is used to identify ongoing inflammatory risk. A reading above 10.0 mg/L typically indicates acute inflammation from another source, like an infection, rather than chronic arterial disease.