More Blood with Arginine

Arginine Promotes Angiogenesis
It’s a potentially valuable adjunct in therapies
designed to improve the heart muscle’s blood supply
By Will Block

© Dumas

et’s say you have a flower bed that’s nourished by drip irrigation through a network of small garden hoses. An obstruction of some sort has clogged the hose that serves the area where the nasturtiums are, and they’re doing poorly. They start crying out to any nearby hoses, “We’re thirsty—give us water!” These cries are carried not by sound waves (nasturtiums can’t talk, you know), but by specialized signaling molecules wafting through the air.

The closest hose listens—and responds in an amazing way. (Did I mention that this was a magical garden?) Tiny buds form on the surface of the hose and quickly elongate into slender cylindrical shapes. These appendages grow (branching out as they go) toward the nasturtiums, and soon they open up and begin dripping water, right where it’s needed. If only you could patent that hose and sell it . . .

And if only you could look inside yourself with a magic microscope, you might see something similar involving your blood vessels. In response to chemical signals crying, “Blood! I need more blood!” coming from a given region of oxygen-poor tissue, small arteries or arterioles sprout new capillary vessels that grow in the direction whence the signals came. Soon they’re bringing additional life-giving blood to the tissue that needed it.

Angiogenesis—A Big Deal when the Chips Are Down

This process—the growth of new blood vessels from existing ones—is called angiogenesis. The chain of molecular events through which it unfolds is a marvel of biochemical and biomechanical beauty. Angiogenesis facilitates the delivery of more blood—hence more oxygen and nutrients—to “dry” areas that request it. Although this process is an integral feature of growth and development, it normally occurs very little in adults, except during wound healing, when new blood vessels are needed to nourish the new tissue, and during the menstrual cycle in women, when new blood vessels form in the uterine lining.

But . . . angiogenesis can also occur in the heart, brain, and other organs if some portion of them is deprived of blood because of an obstruction in the normal blood supply. In such circumstances, as we will see below, the amino acid arginine may be helpful in promoting angiogenesis, which can spell the difference between life and death for the tissue in question. Clearly, angiogenesis is a big deal when the chips are down. To see how big a deal, and to see what happens if its normal control mechanisms are disrupted, causing either too much or too little of it to occur, read the sidebar “The Two Faces of Angiogenesis.”

The Two Faces of Angiogenesis

A developing deer antler is covered by a type of skin called velvet, whose rich network of blood vessels provides oxygen and nutrients to the rapidly growing bone. The velvet’s own growth must, of course, keep up with that of the bone (until the latter reaches maturity, when the velvet withers and drops off), and this requires the constant growth of new blood vessels. In 1787, a British surgeon coined the term angiogenesis to describe this phenomenon.

In time, medical scientists came to recognize the importance of angiogenesis as a general process in animals and humans. They were unprepared, however, for a revolutionary idea put forth in 1971 by the American surgeon and cell biologist Judah Folkman. He suggested that tumors depend critically for their growth on angiogenesis because of their extravagant needs for blood-borne nutrients as they transition from the dormant state to the malignant state. This theory was initially met with disbelief and derision—and with consternation, because it suggested that angiogenesis had a dark side.

It turned out that Folkman was right, however. His studies triggered an explosion of research on angiogenesis, including more than $4 billion (so far) on angiogenesis-based drugs, making this field one of the most heavily funded in the history of medicine. The research is neatly divided into two camps with opposing objectives:

  • Anti-angiogenesis – To inhibit angiogenesis in the body is to attack not only cancer but also a host of other diseases in which the excessive growth of new blood vessels feeds diseased tissues or destroys normal tissues (as, e.g., in the “wet” form of age-related macular degeneration). In the case of cancer, angiogenesis also facilitates metastasis, the process whereby tumor cells escape into the general circulation and lodge elsewhere in the body, starting new tumors.

  • Pro-angiogenesis – Promoting angiogenesis is useful in the treatment of delayed wound healing, such as occurs, e.g., in diabetes. It can also be used to treat two notorious killers: coronary artery disease and stroke. In these conditions, the restoration of proper blood flow is vitally important, and the rate of growth of new blood vessels can spell the difference between life and death of the tissues involved. Thus, insufficient angiogenesis can be a major liability.

I know what you’re thinking: people don’t conveniently have only one medical condition at a time, so if angiogenesis is such an important phenomenon in health and disease, then how do we know when to inhibit it and when to promote it—and with what agents, in what amounts, according to what protocols, etc.? Having to wrestle with such complex questions is one of the reasons why physicians get the big bucks.

Here are a few things they know about angiogenesis (and now you will too). The human body controls this process through a series of “on” switches (angiogenesis factors, of which at least 20 are found in the body) and “off” switches (antiangiogenesis factors, aka angiogenesis inhibitors, of which at least 30 are found in the body). In healthy individuals, there is a perfect balance between these two opposing “armies” of agents, with the off switches dominating.

In many disease states, however, the balance is disrupted by overproduction or underproduction of various agents in one army or the other (or both), resulting in either excessive or insufficient angiogenesis. Collectively, these problems are a common denominator shared by diseases—including cancer, cardiovascular disease, blindness, arthritis, diabetes, Alzheimer’s disease, complications of AIDS, and more than 70 other health conditions—that afflict over 1 billion people worldwide.

Enormous effort is devoted to antiangiogenesis research for the treatment of cancer (more than 300 agents have been discovered so far, and eight have become prescription drugs). Playing catch-up is the burgeoning field of proangiogenesis research, called therapeutic angiogenesis, for the treatment of cardiovascular disease. So far, no drugs have been FDA-approved for such therapy, and most of the research is focused on finding ways to activate the body’s own proangiogenic agents.

Therapeutic Angiogenesis Gives Nature a Helping Hand

The sidebar introduces the concept of therapeutic angiogenesis, which is seen as a promising strategy for treating cardiovascular disease because it augments the body’s own primary response when there is inadequate blood flow to cardiac tissue (the heart muscle itself). That response—similar to but not the same as angiogenesis—is the establishment of collateral circulation to circumvent obstructions in the coronary arteries.

Collateral circulation occurs when existing, minor blood vessels that are normally closed open up to reroute blood flow from the coronary artery around the obstruction, thus maintaining (or trying to maintain) an adequate blood supply to the tissue downstream of the obstruction. It also entails the natural joining of previously separate blood vessels (a process called anastomosis) to serve the same purpose.

For Angiogenesis, Cells Must Grow and Divide

The trouble with collateral circulation is that it’s often inadequate to the task, especially under conditions of physical exertion or emotional stress, which can bring on an attack of angina pectoris (chest pain), or worse. Thus, any additional boost in circulatory capacity, such as through therapeutic angiogenesis, would be a plus in patients with severe coronary artery disease.

The therapeutic agent of greatest interest is a small protein called vascular endothelial growth factor (VEGF), which is produced mainly in the endothelium, the thin layer of smooth, flat cells that line the insides of our blood vessels. These cells are central to the process of angiogenesis, because they’re the building blocks of new blood vessels. Since new vessels require new endothelial cells, existing cells must grow and divide (under the biochemical prodding of VEGF), and keep on doing so, until there are enough to form the new vessel. (Ordinarily, endothelial cells are long-lived, dividing only about once every 3 years.)

VEGF Promotes Angiogenesis

VEGF is a key contributor to angiogenesis in both health and disease. It’s produced not only by endothelial cells (and various other healthy cells) but also, alas, by tumor cells, as you saw in the sidebar. On the plus side, the upregulation (enhanced production) of VEGF is one of the many major physiological responses to physical exercise, which also stimulates the synthesis of the cell-signaling molecule nitric oxide (NO) from its precursor, arginine. (NO plays a central role in blood pressure regulation, among other functions.) Exercise is believed to be the most effective natural stimulator of angiogenesis, which is particularly beneficial for endurance athletes because of their bodies’ extraordinary demands for oxygenated blood.

It’s reasonable to think that therapeutic angiogenesis based on the stimulation of VEGF production would be helpful in alleviating the symptoms of coronary artery disease (CAD). And it is helpful—in animals. In humans, however, the results have been disappointing: although numerous trials have shown promising tendencies, they have consistently failed to produce statistically significant results. There are many possible reasons for this, including, apparently, a placebo effect so strong that it tends to mask any genuine therapeutic effect.

Angiogenesis Also Depends on NO . . .

A team of Canadian cardiologists and cardiac surgeons reasoned that the failure might also be connected with the markedly abnormal coronary endothelial function that is characteristic of severe CAD.1 This dysfunction is due in large part to the decreased availability of NO, a molecule that is never stored in our cells but is synthesized locally (from arginine), on demand, for immediate use. And angiogenesis, as the researchers had themselves previously demonstrated, depends on local NO levels.

Are we connecting the dots? Decreased NO availability . . . endothelial dysfunction . . . impaired angiogenesis . . . blood-deficient cardiac tissue. To see if the dots connect in reality and not just in theory, the Canadian researchers undertook a study of 19 patients with severe CAD who were undergoing the operation called coronary artery bypass graft, or CABG (pronounced cabbage).1 During the operation, the surgeons selected ten strategically important points on the heart muscle, near the coronary arteries being grafted, and injected small amounts of a genetic material called a plasmid, whose DNA would cause additional VEGF to be produced in those areas of the cardiac tissue. In some patients, used as controls, they injected a placebo (saline solution) instead.*

*When a surgical procedure involves the use of a biological therapy (such as VEGF injections into the heart) or the use of natural or synthetic biomaterials (such as joint-replacement materials), we call it biosurgery. Be aware, though, that there is another, very different meaning for this term: it’s used to describe the ancient but recently resurrected medical use of maggots to clean and disinfect putrid wounds by allowing them to eat the dead or decaying tissue (being finicky, they shun healthy tissue). This practice used to go by the charming name of maggot therapy, until some genius in the medical profession decided that biosurgery sounded better.

For 3 months postoperatively, they administered oral arginine (6 g per day) or placebo to the recovering patients. Thus the patients represented four groups (to which they had been assigned randomly): (1) VEGF injections plus oral arginine; (2) VEGF injections plus oral placebo; (3) placebo injections plus oral arginine; and (4) placebo injections plus oral placebo. In this way, the researchers hoped to distinguish genuine therapeutic effects of VEGF, with or without arginine, from placebo effects.

. . . And, Therefore, on Arginine

The primary therapeutic effect they were looking for—an improvement in the perfusion of the heart muscle with blood—can be deduced via measurements of heart-function parameters that are too technical to discuss here. We can recap, however, why the researchers thought they would see this effect with the concomitant use of VEGF and arginine. In animals, endothelial dysfunction (which is characteristic of CAD, remember?) inhibits angiogenesis, and arginine has been shown to reverse this inhibitory effect (via its release of NO), thereby enhancing angiogenesis. And in humans, arginine has been shown to enhance coronary endothelial function, suggesting that it might enhance the efficacy of therapeutic angiogenesis with an agent such as VEGF.*

*For a discussion of arginine’s vital role in maintaining proper endothelial function, see “Arginine Enhances Cardiovascular Health” (March 2008). And for more on VEGF, see the sidebar “The Trouble with VEGF” in the article “Mastic Suppresses Human Leukemia Cells” (December 2006), which discusses mastic’s ability to inhibit VEGF when it exhibits its dark side.

Citrulline Begets (Really Begets) Arginine

A curious fact about arginine is that, when taken orally, it can increase the production of NO in the vascular endothelium, even though it should not be able to, based on what we know about endothelial nitric oxide synthase (eNOS, the enzyme that catalyzes the NO-producing reaction) and the laws of enzyme kinetics. This is called the arginine paradox. It does not mean that the laws are wrong, but only that there’s something else going on with arginine that we don’t fully understand.

Complicating the situation is the fact that arginine can take any of about half a dozen different metabolic pathways, only one of which produces NO. Which way it goes at any moment depends on the circumstances, which are constantly changing. This is a common situation in biochemistry, because of the multiplicity of possible chemical reactions among the thousands of different compounds found in a cell. It’s like a molecular ecosystem, in which a disturbance of the equilibrium anywhere can impact many other factors elsewhere in ways that are difficult to understand, let alone predict.

In contrast to arginine and its plethora of metabolic options is the closely related amino acid citrulline, which has only one metabolic path to follow: it’s converted to arginine.* And unlike arginine, much of which is not bioavailable in the first place (owing to its destruction by intestinal bacteria and by enzymes in the gut and liver), citrulline is readily absorbed. This suggests that supplemental citrulline might be an attractive adjunct to supplemental arginine because, as an arginine precursor with nowhere else to go, it might be a more effective booster of arginine levels than arginine itself.

*Arginine is found abundantly in most protein-rich foods. Citrulline, however, is found mainly in watermelon (Citrullus lanatus) and in casein, which is the principal protein of cow’s milk and the chief constituent of cheese.

But is that true? Apparently it is, according to a team of researchers in Germany and the United States, who have published the first study designed to answer this question.1 Using 20 healthy, nonobese volunteers (average age 57), they studied the effects on plasma arginine levels of different doses of orally administered arginine and citrulline in a randomized, double-blind, placebo-controlled, crossover trial, in which each volunteer served as his or her own control. (Each medication period lasted for 1 week.)

For arginine, the dosages used were 3 g/day (1 g taken thrice) of the immediate-release form and 3.2 g/day (1.6 g taken twice) of the sustained-release form. For citrulline, the dosages were 1.5, 3, and 6 g/day (0.75, 1.5, and 3 g, respectively, taken twice).

The results showed, among other things, that a citrulline dose of 1.5 g/day for 1 week was about as effective at raising plasma arginine levels as was an arginine dose of 3 g/day (immediate-release form) or 3.2 g/day (sustained-release form). Thus, citrulline appears to be about twice as effective as arginine in raising arginine levels. Citrulline was well tolerated by the subjects, with no side effects, and its effects were dose-dependent.

The researchers also sought evidence that the increased bioavailability of arginine brought about by citrulline administration would produce an improvement in endothelial function mediated by the production of NO. This improvement is manifested as increased vasodilation and can be measured in terms of blood flow in the arm under certain experimental conditions. Some previous studies had provided evidence of improvement with arginine or citrulline, whereas others had not. In the new study, the researchers found no such evidence, and they speculated that this might be due to the trial’s very short duration.

Incidentally, only about 1% of orally administered arginine is utilized for NO production, according to the researchers; the rest follows other pathways. In both the NO-producing pathway and one of the others (which produces urea), arginine is converted to citrulline in a cyclic series of reactions that lead, inevitably, back to arginine. That’s because citrulline, as noted above, has no other options.


  1. Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Böger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Brit J Clin Pharmacol 2007;65:51-9.

The Seeds Are Sown

So, did the researchers see the effect they were looking for with the combined VEGF and arginine treatment? Yes, to a small but significant degree, despite the numerous limitations (by their own account) in the design of this complex, challenging study. Although they could not recommend the treatment based on the study results, they saw in the latter the seeds of further research that they believe is likely to strengthen the role of arginine as a safe and effective adjunct to therapeutic angiogenesis, whose potential remains tantalizingly unrealized.

It’s worth noting that therapeutic angiogenesis for cardiovascular disease can be pursued at three different levels: (1) protein therapy, with VEGF or other angiogenic growth factors; (2) gene therapy, which involves manipulation of our DNA to produce angiogenic growth factors; and (3) cell therapy, in which endothelial progenitor cells are implanted to produce angiogenic growth factors. All of these techniques show promise, but none has yet shown significant success. (It’s also worth noting that over the past century, legions of quacks have used the term cell therapy and similar terms to promote all manner of bogus “cures” and “rejuvenation” schemes. Caveat emptor.)

How Doth Your Garden Grow?

While we await further developments in therapeutic angiogenesis, it’s well to remember that supplementation with arginine has been used in a variety of clinical conditions, including high cholesterol, coronary artery disease, congestive heart failure, peripheral arterial disease, and sickle cell anemia, in attempts to improve vascular endothelial function mediated by NO.2 And it’s used in the elderly for the same purpose. You’re never too old to improve your “garden hoses.”


  1. Ruel M, Beanlands RS, Lortie M, Chan V, Camack N, deKemp RA, Suuronen EJ, Rubens FD, DaSilva JN, Sellke FW, Stewart DJ, Mesana TG. Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: The Endothelial Modulation in Angiogenic Therapy randomized controlled trial. J Thorac Cardiovasc Surg 2008;135:762-70.


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