The raised blood pressure of old age is known as hypertension, and it is predominantly caused by dysfunction in blood vessel walls: cross-links, calcification, and loss of elastin cause reduced elasticity, while smooth muscle cells lose their capacity to act for a variety of other reasons. When blood vessels can no longer correctly react to circumstances by contracting and dilating to an appropriate degree, then the whole system of pressure control is thrown off, and higher blood pressure is the result.
Atherosclerosis, on the other hand, is the progressive formation of fatty plaques in blood vessel walls. This narrows and weakens blood vessels. Atherosclerosis interacts with hypertension in the obvious way: weakened blood vessels and fragile plaques are more likely to suffer catastrophic structural failure in a high pressure environment, leading to a fatal stroke or heart attack. Just considering this interaction, it is clear that hypertension raises the risk of death and shortens life expectancy. This isn't the only interaction, however, just the most direct one. In addition, hypertension accelerates the growth of atherosclerotic plaques, and the reasons for this are not fully understood.
In the research materials noted here, the authors report on an association between a particular subset of cases of hypertension and the pace at which immune cells known as monocytes arrive at atherosclerotic plaques in order to try to clean them up. Once embedded into the blood vessel wall, monocytes transform into macrophages. Plaques grow because these macrophages become overwhelmed by oxidized lipids, fail in their task of rescue, and die. Worse, many become inflammatory, senescent foam cells that linger to secrete signals that call in more of their peers. The bulk of a plaque is cell debris, and atherosclerosis is really a form of runaway garbage catastrophe. Once things get to the tipping point, the end is inevitable. In some cases, hypertension moves that tipping point in an undesirable direction by causing the production of more monocytes.
Atherosclerotic cardiovascular disease is a build-up of cholesterol plaque in the walls of arteries, causing obstruction of blood flow. Scientists have found that high blood pressure caused by specific signalling from the brain promotes heart disease by altering stem cells within the bone marrow. The results demonstrate how an overactive sympathetic nervous system that causes elevated blood pressure can instruct bone marrow stem cells to produce more white blood cells that clog up blood vessels.
"We now know that changes in the immune system contribute significantly to heart disease. We aimed to determine how the sympathetic nervous system through the brain directly promotes atherosclerosis in the setting of hypertension. We have discovered that this form of high blood pressure, often associated with stress, causes changes within the bone marrow leading to increased white blood cells circulating though our vessels. This is significant as the general view of hypertension is that it is mainly a disease of the blood vessels, which means other heart damaging events are missed." The team is now exploring the specific molecules involved, which may shed light as to why some current therapies are ineffective.
Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E deficient background. When mice were placed on a western type diet for 16 weeks we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms.
With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells, and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.