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UCLA Cardiovascular Research Theme

Atherosclerosis & Vascular Biology

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  3. Atherosclerosis & Vascular Biology

Building Healthy Vessels

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Investigators at UCLA working on the vascular side of cardiovascular disease know the blood vessel system is not just plumbing. In fact, our scientists are leading the way in understanding the difficult and fascinating extent to which our vascular systems differ, and the implications for preventing and curing vascular disease.

Vascular Complexity Leads to New Discoveries at UCLA

Dr. Luisa Iruela-Arispe

Dr. Luisa Iruela-Arispe

The arteries, veins and capillaries are amazingly complicated. “They are pipes, but there is a lot of power in those pipes,” says Dr. Luisa Iruela-Arispe, professor and vice-chair of Molecular, Cell & Developmental Biology
She notes that:

  • Vascular biology differs from person to person, even between identical twins.
  • Vessels in the brain are distinct from those in the liver and the kidney and the heart.
  • In some cases, blood vessels tell other cells in an organ what to do.
  • Epigenetic differences are factors that influence the expression of genes, but do not involve mutations. These differences, in multiple genes that regulate blood vasculature, can even be seen in identical twins. Doctors have noted these changes when twins have equally high cholesterol levels, but one develops atherosclerosis and the other does not.

Tumors “Tickle” Blood Vessels  

Tumor angiogenesis (Image courtesty of Iruela-Arispe Lab)

Tumor angiogenesis (Image courtesty of Iruela-Arispe Lab)

Dr. Iruela-Arispe is among a group of UCLA researchers focused on revealing the molecular mechanisms of how blood vessels develop.

This basic information may be used clinically to enhance the growth of blood vessels, such as for treatment of heart attacks or for wound healing, or to prevent growth, in the case of cancer. For example, cancer cannot spread without actually getting inside a blood vessel and then exiting it.

A postdoctoral physician researcher in her lab, Dr. Georg Hilfenhaus, has found that essentially, tumors “tickle” blood vessels. Also, the vessels respond by opening to let tumor cells in or out and in experiments, compounds actually seal the endothelium – the lining of the vessel. This sealant makes vessels impermeable to penetration by tumor cells.

Saving “Blue Babies” Reveals Vascular Mysteries

The complexity of the vascular system can be seen in the case of young adults who were “blue babies” at birth – lacking enough oxygen to feed their bodies.

Over decades of research, doctors have found that:

  • Infant deaths are preventable: New surgical techniques reroute these babies’ vasculature – an advancement that has almost eliminated infant death from the disorder.
  • Problems arise in adulthood: When one-time “blue babies” reach their 20s and 30s, problems may arise. Their blood vessels are routed abnormally within the body. While the lung normally receives the blood from the liver, in these cases, it doesn’t. These individuals start coughing up blood, and some of them die.
  • The problems that arise later in life have taught researchers that:
    • The content of the blood that comes from the liver is vital to maintaining the stability of those vessels.
    • Vessels in the kidney require different biological compounds than vessels in the lung

eNOS: A Jekyll-and-Hyde Molecule

One explanation for variability in vascular biology may be linked to nitric oxide, long a topic of research at UCLA. In fact, Dr. Louis Ignarro, now professor emeritus in molecular and medical pharmacology, received the Nobel Prize in Physiology/Medicine in 1998 for his work demonstrating the signaling properties of nitric oxide (NO).

Dr. Linda Cai

Dr. Linda Cai

A question facing cardiology experts is whether an enzyme, endothelial nitric oxide synthase (eNOS), plays a positive or negative role in regulating the innermost lining of blood vessels, says Dr. Linda Cai, professor of anesthesiology and medicine (cardiology) and director of the Department of Anesthesiology’s Translational Research Program.

Dr. Cai’s team has made several discoveries about eNOS:

  • How eNOS works in healthy conditions: When eNOS is healthy, it produces endothelial NO to dilate blood vessels and inhibit pathological events. It is a very powerful protector of vascular health because it protects the integrity of the vessels.
  • When eNOS becomes dysfunctional: Dr. Cai and her colleagues found that eNOS can become dysfunctional because of normal aging, smoking or conditions such as hypercholesterolemia. In these cases:
    • It produces reactive oxygen species – toxic small molecules – that can cause significant damage to the vessel.
    • Loss of healthy eNOS leads to high blood pressure, aortic aneurysms and atherosclerotic vascular disease.
    • eNOS becomes a pro-oxidant rather than an antioxidant enzyme. These reactive oxygen species play a large role in all kinds of heart and vessel disease.
  • Healthy eNOS can be restored: Investigators have discovered that in animals, healthy eNOS can be restored via a newly identified pathway. This pathway uses folic acid, a B vitamin found in many fresh fruits and vegetables, especially uncooked green leafy vegetables. Folic acid helps synthesize and repair DNA.

Dr. Cai and colleagues are now conducting human studies to reveal underlying mechanisms of eNOS dysfunction and to develop new therapies in a preclinical setting.

Food’s Impact on Vessels

Many common diseases involve chronic inflammation, but in vascular disease, inflammation is key.

Dr. Jake Lusis, who studies the complex genetic traits underlying cardiovascular and metabolic disorders, lays out the connection:

  • Cholesterol accumulates in arteries.
  • Inflammatory cells enter the vessel wall and produce a chronic inflammatory response.
  • This response leads to a lesion.
  • When this lesion ruptures, a heart attack can result.

The Red Meat-Heart Disease Connection

UCLA researchers are studying how common foodstuffs harm blood vessels. This work is part of our efforts to expand the understanding of the interactions between nature and nurture – genes and the environment.

Dr. Lusis, in collaboration with investigators from Cleveland Clinic, has discovered how the gut microbiome can cause inflammation in the heart. Articles published in Cell in December 2015 and in the Journal of the American Heart Association in February 2016 show:

  • The toxic molecule, trimethylamine N-oxide, is derived through the action of gut bacteria.
  • Investigators traced TMAO back to consumption of red meat.
  • TMAO activates cells in blood vessels in the heart, producing inflammation.
  • A naturally occurring, non-toxic molecule can inhibit the production of TMAO in gut bacteria.

This research is just the beginning of learning how gut bacteria can protect the heart.

Cholesterol-Lowering Fruit

Another group of scientists has demonstrated how tweaking another food – actually a fruit – can improve a mouse’s cholesterol profile.

Researchers at UCLA conducted experiments in mice bred to develop inflammation and atherosclerosis. In these experiments:

  • Scientists inserted genes into tomatoes so that they produce a peptide, 6F, which mimics the actions of apoA-1, the main protein in high-density lipoprotein (HDL), also called good cholesterol. HDL helps mitigate harmful effects on blood vessels from low-density lipoprotein (LDL), the bad cholesterol.
  • The peptide altered intestinal lipid metabolism.
  • These effects in turn significantly lowered levels of inflammation and plaque formation in the arteries

According to Dr. Alan Fogelman, chair of Medicine and director of the Atherosclerosis Research Unit at the David Geffen School of Medicine, researchers are still trying to determine exactly how the peptide functions in animals, so don’t expect HDL tomatoes in the supermarket anytime soon. Still, the study is the first report in which a peptide has been engineered into food to reduce plaques and inflammation in the blood vessels of those who eat it.

Consequences of “Hardened” Arteries

UCLA research has helped to identify the process that underlies “hardening” of blood vessels.

It has long been known that bone tissue and even marrow can form in the walls of human arteries, usually near cholesterol deposits.

Dr. Linda Demer

Dr. Linda Demer

Previously, says Dr. Linda Demer, vice chair of Medicine, artery wall calcification was considered a passive degenerative process. Now, work in Demer’s lab and in others indicates that artery wall cells actively form calcium deposits in much the same way that skeletal bone cells form mineral.

Together with Dr. Yin Tintut, Dr. Demer directs the Cardiovascular Biomineralization Research Group. In collaboration with UCLA engineers, they found:

  • The process of calcification in the artery wall is similar to embryonic bone formation.
  • There is increased risk of rupture along the edges of calcium deposits facing mechanical stress.
  • By isolating and cloning the artery wall cells responsible for producing calcium mineral and by identifying the regulatory molecules controlling the process by which these cells differentiate into bone-like cells, investigators developed the first cell-based model of vascular calcification.
  • Based on comparisons to cells from the skeleton, high cholesterol may contribute not only to atherosclerotic calcification, but also to osteoporosis.

Whether calcium deposits protect against, or increase the likelihood of, rupture of coronary plaques – and resulting heart attacks – is a question debated in the cardiovascular disease research community. This research is essential because of the widespread prevalence of vascular calcification, which promotes heart failure and hypertension. 

Plaque: Up Close and Active

Dr. Tzung Hsiai

Dr. Tzung Hsiai

While Dr. Demer has used culture models to study plaque, the engineering side of cardiologist Dr. Tzung Hsiai, professor of bioengineering and medicine (Cardiology), favors a more direct approach. He wants to get into the heart and “look around” to identify the risks associated with plaque and blood clots.

Dr. Hsiai and his group have developed flexible sensors that assess the pattern of blood moving around arterial plaque. The sensors work this way:

  • In animals, sensors can measure changing forces in the plaque in response to changing blood flow around it.
  • Certain blood profiles can indicate that a clot is biologically active and unstable. These unstable clots are more likely to rupture, causing a heart attack. Clots are extremely unpredictable. For example:
    • Some people with a clot that blocks 75% of an artery will have chest pain but never experience a heart attack.
    • Much more common are patients with plaques that occlude a vessel by only about 30% but who die or suffer lifelong damage from a heart attack or a stroke that neither they nor their physicians saw coming.

The aim of Dr. Hsiai’s program is to use these sensors while a coronary angiogram is underway. (An angiogram is an X-ray image of the blood vessels that supply the heart. The image reveals which vessels are functioning normally and alerts the physician when a blockage is happening.)

Benefits of the sensors may include:

  • Enhanced diagnostics: These sensors can be added on to an existing diagnostic tool. Dr. Hsiai believes this may reduce procedural time, without adding cost, because cardiologists will gain substantial additional information from the sensors to improve their diagnosis.
  • Biological analysis: These sensors also could assess the biology of the plaque. Sensors can detect the presence of different kinds of cholesterol that are metabolically active, as well as the degree of calcium buildup.

 

 

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