Circulatory Function and Vascular Integrity

Supporting vascular integrity to enhance circulatory function

March 27, 2008

36 Min Read
Circulatory Function and Vascular Integrity


Cholesterol is the focus of the majority of research and product development in the cardiovascular category. However, there are many integrated facets of heart health beyond just cholesterol reduction. Consider blood and the vessels that transport it throughout the body. The systemic circulatory system provides nourishment to the entire body, a conduit of arteries and veins, with microscopic capillaries enabling the exchange of water and chemicals between the blood and tissues. It is estimated that the average human body contains enough blood vessels that, if laid end to end, they would stretch more than 60,000 miles. Blood vessels do not actively transport blood, but the diameter of their interior endothelial lining is regulated by contraction of the blood vessels’ muscular layers. Vasoconstriction occurs when the vascular muscles flex, narrowing the tubing; vasodilation is the opposite, a relaxation of the muscles. The most well-known vasoconstrictors include prostaglandins, hormones such as vasopressin and angiotension, and neurotransmitters like epinephrine. On the dilation side, nitric oxide (NO) is the most prominent player.

Endothelial cells are also involved in blood clotting, both thrombosis and fibrinolysis. In addition, the body employs a process known as haemostasis to control bleeding in the vessels. A combination of vascular spasm, which cuts off blood flow to the area, and clotting are employed to protect vessel integrity. The platelets, specialized blood cells, release granules that contain clotting factors and growth factors, while signaling aggregation (sticking other platelets together) to create a plug or clot.

In order to prevent the clot from getting too large, the chemical fibrin works to absorb and inactivate clotting factors, keeping the plug localized. Fibrinolysis is the process of dissolving a clot, in which plasminogen in the clot is activated by the endothelium to become plasmin or fibrinolysin to digest the fibrin and inactivate clotting factors.

Just keeping the vessels and blood healthy is a complex task for the body. The endothelium should be reactive and elastic to allow passage of blood, while the blood itself cannot be too sticky or viscous, which could impede circulation and undermine vascular health. Fortunately, there are a host of nutritional compounds that can support the structure of the blood vessels, enhance the reactivity of the vessels, and address blood viscosity to avoid thrombosis.

Not surprisingly, the health of the vascular system begins with the diet. Studies consistently show following a more Mediterranean-style diet—high in fruits and vegetables, whole grains, polyunsaturated fats and fish—is beneficial to the circulatory system. German reviewers noted such a diet has synergistic activity on haemostasis, endothelial function and vascular inflammation.1 Further, a review out of Pennsylvania State University, University Park, examined the impact of antioxidant foods on vascular health and found dietary consumption of fruits and vegetables, red wine, tea, chocolate and olive oil may improve vascular reactivity and positively impact endothelial function.2

Population and intervention studies support the theory. Boston researchers examined data from 690 women in the Nurses’ Health Study and found higher diet quality scores—particularly on the Mediterranean Diet Index—were associated with lower concentrations of markers of endothelial dysfunction and inflammation.3 A team out of Spain examined the chronic effect of three diets—Western, Mediterranean or low-fat enriched in alpha-linolenic acid (ALA)—on postprandial endothelial function and inflammation in 20 healthy men.4 The Mediterranean diet, rich in monounsaturated fatty acids (MUFAs), had the greatest positive effect on endothelium-dependent vasodilatory response and NO bioavailability, while also significantly lowering plasma levels of vascular cell-adhesion molecule. Similar findings were reported by another Spanish team, which found adding walnuts (rich in MUFAs) to a high-fat meal could improve flow-mediated dilation (FMD) and decrease plasma concentrations of inflammatory cytokines and adhesion molecules.5

Omega-3 essential fatty acids

(EFAs) are a key part of the Mediterranean diet, and other dietary studies have shown their benefit to cardiovascular health. A Canadian research review noted greater intake of omega-3 fatty acids can benefit inflammation and thrombosis, and improve endothelial function.6 French reviewers seconded the findings, suggesting omega-3s reduce platelet aggregation, have anti-thrombotic and fibrinolytic activities, and reduce blood viscosity.7 Recent research on the impact of fish oil fatty acids found adding 9 g of fish oil to a meal increased endothelial nitric oxide synthase (eNOS) expression in endothelial cells and improved vascular reactivity.8 Further, a 14-day study on fish oil supplementation (1 g/d) found it could significantly increase both endothelium-dependent and -independent vasodilation.9

Healthy diets are also rich in basic nutrients, such as vitamins C and E. Vitamin C’s support of vascular health is well-known, as it was the key compound that kept scurvy at bay; adequate vitamin C stores support collagen synthesis, which is key to the integrity of the vascular wall. Studies have found higher dietary and plasma vitamin C concentrations are associated with lower plasma levels of inflammatory biomarkers and of markers of endothelial dysfunction.10 In vitro research suggests vitamin C works by protecting endothelial cells from oxidative stress, thereby preventing endothelial dysfunction;11 it may also promote regeneration of the endothelium after injury.12

A clinical trial from the Medical University of Vienna, Austria, examined whether vitamin C could prevent ischemia-reperfusion-induced endothelial dysfunction in men.13 Volunteers received intra-arterial placebo or 24 mg/min vitamin C co-administered with vasodilators to induce forearm ischemia; vitamin C prevented induced vasodilation, protecting endothelial function.

Bioavailability of vitamin C in dietary supplements is an important issue. Unpublished research on PureWay-C® (from Marco Hi-Tech) suggests the novel formulation of vitamin C lipid metabolites is more rapidly absorbed in the body and retained for longer periods than other forms of vitamin C. Enhanced bioavailability ensures the vitamin C has more time to impact inflammatory and endothelial health.

Combinations of antioxidant vitamins may have synergistic beneficial effects. Croatian researchers examined the effect of pretreatment of open sea air divers with vitamins C (2 g) and E (400 IU); diving has been found to lead to arterial vasodilation and impairment of endothelium-dependent vasodilation.14 Antioxidant treatment prevented dive-induced FMD reduction and endothelial dysfunction. A study out of Athens University Medical School, Greece, found providing healthy smokers with 2 g/d vitamin C plus 400 IU/d vitamin E could improve endothelial function and reduce plasma levels of thrombotic and fibrinolytic factors.15

Vitamin E on its own may also benefit vascular health. A study of 37 patients with type 2 diabetes found supplementation with 500 IU/d of vitamin E could normalize NO bioavailability and increase normal fibrinolysis, supporting healthy endothelial function.16 And an in vitro study showed alpha-tocotrienol works to reduce the expression of cellular adhesion molecules and monocytic cell adherence.17

Another critical vitamin for vascular health is vitamin K. Vitamin K-dependent proteins, including matrix Gla-protein (MGP), have been shown to inhibit vascular calcification. However, activation of these proteins requires bioavailable vitamin K. The population-based Rotterdam study examined the heart health benefits of dietary vitamin K and its role in preventing coronary heart disease (CHD).18 The study involved more than 4,800 people over 10 years, and revealed increased dietary intake of vitamin K2 (menaquinone) significantly reduced the risk of CHD mortality by 50 percent compared to low dietary K2 intake, and also was inversely related to severe aortic calcification. Intake of vitamin K1 (phylloquinone) had no impact.

The results were confirmed in an animal trial in which rats received a diet that exhausted their vitamin K stores, inactivating vitamin K-dependent proteins, which led to major arterial calcification.19 Supplementation with vitamin K2 completely inhibited arterial calcification. Another animal study at the University of Maastricht found in rats with arterial calcification the total amount of aortic calcium decreased by 37 percent in six weeks following a high vitamin K2 diet.20

Follow-up work by the team confirmed natural vitamin K2 (as menaquinone-7, MK-7) was the most effective form of vitamin K, due to its long-chain structure, which results in a half-life of three days; the half-life of short-chain vitamin K2 (MK-4) is only one hour.21

B vitamins are also involved in circulatory wellness. Harvard researchers note the use of niacin to increase high-density lipoprotein (HDL) cholesterol has a role to play, as HDL possesses anti-thrombotic activity and prevents negative effects of low-density lipoprotein (LDL) cholesterol on endothelial function.22 Another study in patients with metabolic syndrome (n=50) found administration of extended-release niacin (1,000 mg/d) improved endothelial function by 22 percent, decreased inflammatory biomarkers and improved carotid intima-medial thickness (IMT).23 Similarly, a study from Walter Reed Army Medical Center, Washington, DC, found providing extended-release niacin to patients on statin monotherapy also had regression of carotid IMT.24

Additionally, folate supports vascular health, increasing NO-mediated endothelial-dependent vasodilation.25 It may also improve platelet function, boosting their ability to produce NO.26 Folate supplementation has shown benefits in patients with chronic health conditions, as well. In a Chinese study of renal transplant recipients, folate helped improve endothelium-dependent and -independent vasodilation responses while also helping to decrease blood homocysteine levels.27 And researchers from the University of Maryland School of Medicine, Baltimore, report providing folate (5 mg), B6 (100 mg) and B12 (1 mg) to patients with prior ischemic stroke helped reduce markers of endothelial injury.28

Studies link coenzyme Q10 (CoQ10) to improved vascular health. Italian researchers noted CoQ10 is best known for its role in mitochondrial function; however, it also appears to help reduce cardiac contractility and endothelial dysfunction, while improving FMD.29 A study in patients with coronary artery disease (CAD) found supplementation with CoQ10 (300 mg/d) could improve endothelium-dependent vasodilation, possibly through its antioxidant effects, protecting NO from oxidation.30 Further work by the Italian team also demonstrated adding CoQ10 (300 mg/d) to patients with chronic heart failure (CHF) could improve functional capacity, endothelial function and ventricular contractility.31

Another basic nutrient with a critical role to play in the circulatory system is the amino acid L-arginine. Reviewers from Brigham & Women’s Hospital, Boston, noted L-arginine is required by eNOS to produce NO, and administration of L-arginine in several animal and clinical trials has shown its ability to improve endothelial function.32 One such trial was conducted at Baylor College of Medicine, Houston, in which deep vein thrombosis (DVT) was created in animals, which were then randomized to have the thrombus removed mechanically with or without intravenous L-arginine.33 Adding L-arginine to the treatment decreased platelet deposition and increased endothelium-dependent relaxation. Another study, out of the University of Torino, involved type 2 diabetics (n=24) who received L-arginine plus N-acetylcysteine (NAC) for six months; intervention helped reduce arterial blood pressure and IMT, and increased NO bioavailability.34

Potent Plants

The plant kingdom supplies a cornucopia of options, packed with phytochemicals. One of the best known for its impact on the cardiovascular system is the grape. Studies have looked at the benefits of grapes via red wine, grape seed extract, and even delved into its specialty compound resveratrol. English researchers noted in a review that regular consumption of red wine is linked to a reduced risk of heart disease, and it is likely the polyphenols supply vasoactive support.35 In vitro, red wine and grape seed extract inhibits platelet aggregation and activation by stimulating certain cell adhesion molecules, an activity attributed to its polyphenol content.36,37 Researchers from the University of South Florida, Tampa, also found grape seed extract has endothelium-dependent relaxing activity, related to NO release.38

Studies out of the University of California, Davis, have sought to examine the effects of a specific grape seed extract on endothelial function and arterial pressure. In an in vitro study, researchers applied GSE (as MegaNatural BP®, from Polyphenolics) to rabbit aortic rings, and found the extract could produce a dose-dependent relaxation when the rings were contacted with noradrenaline.39 Relaxation was inhibited by removal of the endothelium, underscoring the role of eNOS in the response; the extract was also found to activate the P13K/Akt signally pathway, resulting in phosphorylation of eNOS.

Clinical work by the team supports the efficacy of MegaNatural BP. In a 2006 study, 24 adults diagnosed with metabolic syndrome received a placebo, or 150 mg/d or 300 mg/d of the patented GSE.40 After one month, the participants taking GSE had reductions in systolic and diastolic blood pressure. A two-month follow-up study involved pre-hypertensive subjects who received 300 mg/d of MegaNatural BP or placebo. Those on the intervention had a significant decrease in systolic and diastolic blood pressure, which the researchers attributed to the vasodilation effects of the GSE polyphenols.

Another branded standardized grape seed extract complexed with soy phosphatidylcholine (as Leucoselect™ Phytosome®, from Indena) has been investigated for its impact on arterial health. One study on the extract found it improved the antioxidant capacity of plasma in animals and in humans.41 Another Italian double blind, randomized, crossover study investigated the impact of Leucoselect (150 mg/d) or placebo in healthy male heavy smokers (n=24).42 Supplementation significantly improved oxidative indices and plasma antioxidant defense.

As mentioned earlier, the compound resveratrol, a polyphenolic compound found in grapes, peanuts and some berries, has been considered one of the active polyphenols responsible for the benefits of grape seed extract. French researchers report among different fractions of grape seed extract, the one richest in trans-resveratrol was the most active in relaxing pulmonary arteries, acting directly on smooth muscle, in an in vitro study.43 A study in Taiwan found resveratrol, at low concentrations, could enhance the inhibitory activity of prostaglandins on platelet aggregation.44 Researchers from the University of Waterloo, Ontario, examined the impact of resveratrol (low or high intake) on vasomotor function of rat aorta.45 Chronic consumption of resveratrol significantly improved endothelium-dependent vasodilation in spontaneously hypertensive, but not normotensive, rats; the researchers attributed the activity to improved NO bioavailability.

Another beneficial beverage for vascular health is tea. A review from the University of Western Australia, Perth, noted tea is one of the major contributors to flavonoid intake in most populations, and its flavonoids possess vasodilator activity, working to improve endothelial function.46 Both black and green tea appear to contribute beneficial flavonoids that enhance vascular health.47 For example, Iranian researchers examined the impact of consuming 0.5 L black tea on endothelial function in renal transplant recipients.48 Black tea consumption improved endothelium-dependent arterial vasodilation as well as brachial arterial diameter and FMD.

However, more research has focused on green tea and, specifically, the catechin epigallocatechin gallate (EGCG). Researchers from the National Center for Complementary and Alternative Medicine (NCCAM), NIH, Bethesda, Md., reported on in vitro research showing EGCG has endothelial-dependent vasodilator actions that are mediated by intracellular signaling pathways that activate eNOS.49 Further, Korean researchers report EGCG has dose-dependent anti-thrombotic activities, primarily by inhibiting platelet aggregation rather than impacting coagulation.50 And a clinical trial out of the Boston University School of Medicine found acute supplementation with EGCG (300 mg) in patients with coronary artery disease (CAD; n=42) significantly improved brachial artery FMD and endothelial function.51

Green tea also has an inhibitory effect on iNOS expression in a concentration-dependent manner, according to in vitro work by Italian researchers in two human epithelial cell lines.52 It also had auxiliary anti-inflammatory effects in that trial. A specialty green tea extract (Greenselect®, from Indena) specifically appears to protect cardiac myocytes from cell death after ischemia, which enhanced the recovery of ventricular function and hemodynamic recovery.53

Originally enjoyed as a beverage, chocolate has come into its own as a tasty snack with health benefits. A review from Athens Medical School, Greece, noted dark chocolate and flavonoid-rich cocoa have beneficial acute and short-term effects on endothelial function, probably related to flavonoid content and mediated through increased NO bioavailability.54 In vitro, cocoa flavanols also modulate platelet function, inhibiting aggregation and activation, while also inhibiting monocyte and neutrophil activation.55,56

Researchers at the University of California, Davis, investigated whether chronic dietary consumption of flavonol-rich cocoa could improve endothelial function in hypercholesterolemic postmenopausal women (n=32).57 Over the course of the six week, double blind study, women consumed a high-flavanol (446 mg) or a low-flavanol (43 mg) cocoa beverage. Brachial artery blood flow increased by 76 percent in the high-flavanol group, and by 32 percent in the low-flavanol group; the 2.4-fold increase among the high flavanol consumers correlated closely with a decrease in plasma levels of vascular cell adhesion molecule-1. German researchers found similar results in a seven-day study, in which 900 mg/d flavanols in a cocoa drink increased FMD and plasma nitrite levels.58 In a Swiss study, acute consumption of flavonoid-rich dark chocolate (40 g) by heart transplant patients induced coronary vasodilation, improved vascular function and decreased platelet adhesion.59

Another tasty treat with helpful qualities is olive oil, cited earlier for its role in the Mediterranean diet. Researchers from the Instituto de la Grassa, Seville, Spain, noted some of the minor components of virgin olive oil, such as polyphenols, sterols and triterpenoids, found in trace amounts may have specific activity on vascular dysfunction and may help modulate endothelial activity.60 Among their cited activities are the release of NO, impact on adhesion molecules, and anti-inflammatory properties. The same research team investigated the impact of dietary pomace olive oil, with a higher proportion of oleanolic acid (OA), in rats; chronic intake of OA-rich olive oil increased eNOS protein expression and improved endothelial dysfunction.61 Olive oil may also benefit the blood itself, as an Italian in vitro study found olive oil flavonoids could inhibit aggregation of human platelets, with the flavonoids luteolin and oleuropein aglycone showing the most activity.62

Another botanical found in the Mediterranean is citrus; its flavonoids have been studied and used pharmaceutically for treatment of vascular dysfunction. Greek researchers reported a micronized purified flavonoid fraction delivering hesperidin and diosmin (as Daflon) has the ability to inhibit endothelial activation, prevents inflammation linked to chronic venous insufficiency (CVI), protects microcirculation and prevents capillary damage.63 A comparative study out of France found Daflon was more effective than just diosmin in supporting microcirculation in an animal model, decreasing permeability of the capillaries.64 Australian researchers have also reported Daflon can help alleviate symptoms of CVI and protects the microcirculation from inflammation, reducing capillary hyperpermeability.65

Italian researchers compared the efficacy of Daflon (1,000 mg/d) to 150 mg/d or 300 mg/d of French maritime pine bark extract (as Pycnogenol®, from Natural Health Science) in a group of 86 patients with severe CVI.66 After eight weeks, Pycnogenol intervention reduced ankle swelling by 35 percent and edema by 64 percent, compared to 19 percent and 32 percent reductions, respectively, in the Daflon group. Additionally, there were no significant differences between the 150 and 300 mg/d dosages. Another study on patients with CVI found Pycnogenol (150 mg/d) improved the level of microangiopathy, significantly decreased capillary filtration and reduced edema.67

Another trial involved 60 diabetic patients with microangiopathy, a condition in which capillary walls become thick and weakened, bleeding and leaking protein.68 Patients received 150 mg/d of Pycnogenol or placebo for one month, and capillary blood flow measurements taken when the subjects were lying down and standing up. Intervention improved capillary blood flow when lying down by 34 percent, compared to 4.7 percent in the placebo group; when subjects were standing, there was a 68-percent improvement in capillary blood flow, compared to 8 percent in the placebo group. Treatment with Pycnogenol also improved capillary leakage, reducing ankle swelling by 17 percent after passing from lying down to standing up, compared to 2.6 percent in the placebo group.

Berries also support the vascular system. Indiana University researchers examined the vasoactive and vasoprotective properties of three anthocyanin-enhanced extract prepared from chokeberry, bilberry or elderberry (supplied by Artemis International) in swine coronary arterial rings.69 Chokeberry and bilberry produced dose- and endothelium-dependent vasorelaxation; in addition, low doses of the extracts protected the arteries from oxidative damage.

Another botanical “berry,” the tomato, delivers powerful support through its high lycopene content, as well as synergistic nutrients. Researchers from the Rowett Research Institute, Aberdeen, Scotland, conducted a randomized, double blind, placebo-controlled, crossover study in which 90 healthy adults received tomato extract equivalent to two or six tomatoes.70 A dose response to tomato extract was found at low levels of platelet stimulation, with the extract inhibiting platelet activation. Follow-up work by the researchers found tomatoes contain anti-platelet compounds that inhibit thrombin-induced platelet aggregation in addition to adenosine.71

Italian researchers investigated the effects of lycopene alone, with alpha-tocopherol or whole tomato lipophilic extract on endothelial cell function.72 Lycopene increased biosynthesis of platelet-activating factor only when it was found with alpha-tocopherol or the compounds in the whole lipophilic extract, leading the researchers to suggest several compounds work synergistically to modulate the atherogenic process in the vascular endothelium. Another study out of University of the Negev, Beer-Sheva, Israel, examined the impact of 250 mg/d tomato extract (as Lyc-O-Mato®, from LycoRed Ltd.) on blood pressure and oxidative stress markers in 31 subjects with grade-1 hypertension.73 After the eight week intervention, systolic and diastolic blood pressures decreased, as did markers of lipid peroxidation.

The plant kingdom also offers beneficial botanicals. Garlic, for example, was found in an animal study at the University of Alabama at Birmingham to protect against increased ventricular pressure via the metabolite allicin’s activity on endothelial function and vasoreactivity.74 In fact, the endothelium-modulated vasorelaxation may be mediated through the cyclooxygenase (COX) pathway, beyond NO.75 Garlic may also modulate the expression of endothelial leukocyte adhesion molecules, preventing monocyte adhesion.76

Aged garlic extract (AGE) has also been the subject of study. In a placebo-controlled, crossover pilot study, pretreatment with 4 mL/d of AGE (as Kyolic® AGE, from Wakunaga) for six weeks significantly improved the endothelial dysfunction induced by acute hyperhomocysteinemia in macro- and microvascular systems.77 The researchers noted Kyolic AGE may be useful for maintaining or improving blood vessel function and blood pressure and circulation by preventing a decrease in bioavailable NO and endothelium-derived hyperpolarizing factor.

Additional studies support the theory. A randomized, placebo-controlled, crossover design study in which 15 men with CAD took Kyolic AGE (2.4 g/d) for two weeks found a 44 percent increase in FMD.78 In a double blind, randomized clinical study, Kyolic AGE (5 mL/d) taken for 13 weeks by normocholesterolemic adults significantly reduced clotting—both clotting rate and amount—induced by a clotting agent.79 Another randomized, double blind clinical trial in moderately hypercholesterolemic men found administration of Kyolic AGE (2.4 and 4.8 g/d) reduced blood levels of LDL and total cholesterol by 5 to 7 percent.80 Kyolic AGE also reduced platelet aggregation induced by collagen and epinephrine, and inhibited its adhesion to fibrinogen and collagen. Blood pressure was also reduced.

Ginkgo biloba

, a Chinese botanical, is best known for its purported impact on memory, which may be mediated by increased blood flow to the brain and reduced blood viscosity.81 Chinese researchers tested the impact of ginkgo extract on FMD in patients with CAD (n=80), and found the botanical could increase arterial blood flow in connection with improved endothelium-dependent vasodilatory capacity.82 In vitro work also illustrates Ginkgo biloba extract (as EGb-761) can inhibit induced endothelial dysfunction.83 Ginkgo also impacts platelet function, preventing monocyte adhesion to endothelial cells.84

A phytosome complex of Ginkgo biloba extract (as Ginkgoselect® Phytosome®, from Indena) appears to not only have antioxidant effects but work on vascular disorders. Researchers from Ninewells Hospital & Medical School, Dundee, Scotland, investigated the efficacy of the extract in treatment of Raynaud’s phenomenon (RP), a painful condition characterized by digital ischeaemia, which manifests as blanching caused by artery vasospasm.85 In their 10 week trial, subjects received active or placebo treatment; those on active treatment saw a significant reduction (56 percent) in frequency and severity of attacks. Animal studies on Ginkgoselect further show it can increase the bioavailability of the ginkgo phenolic antioxidants and help repair ischemia/reperfusion damage.86

The Cochrane Database recently updated its review on hawthorn (Crataegus) for chronic heart failure, finding the botanical does have benefits to the cardiovascular system.87 Chinese researchers found hawthorn extract contains active compounds that may increase NO bioavailability and increase vasorelaxation in vitro.88 Further in vitro work suggests hawthorn can protect endothelial cells from thrombus formation, possibly by impacting NO and calcium ion levels.89 Another study in cultured endothelial cells found hawthorn extract was able to inhibit increased synthesis of endothelin-1 and induce endothelium-dependent vasodilation.90

Soy isoflavones may also have a beneficial impact on vascular health. A study out of Stanford University, Calif., examined the effects of dietary isoflavones (as Novasoy®, from ADM) on vascular reactivity, lipid levels and inflammatory markers in post-menopausal women (n=40).91 Six weeks of supplementation with 90 mg/d of isoflavones improved endothelium-independent vasodilation; there was also a trend toward improvement of flow-mediated vasodilation, and endothelium-dependent response.

Danish researchers conducted a randomized, double blind, placebo-controlled, crossover study with 30 postmenopausal women who received cereal bars, with or without soy isoflavones (50 mg/d) for eight weeks, separated by an eight-week washout period.92 Isoflavone treatment significantly improved systemic arterial compliance and endothelium-independent vasodilation, while increasing plasma concentrations of NOx.

Similarly, a study from the University of California, Davis, found when healthy postmenopausal women (n=28) consumed soy protein with isoflavones, it improved vasodilatory response.93 And Italian researchers found providing postmenopausal women (n=60) with isoflavone supplements significantly improved endothelium-dependent vasodilation and reduced plasma adhesion molecule levels.94

The mechanisms of action are still being elucidated. However, in vitro studies suggest the isoflavones have direct nongenomic effects on eNOS activity in vascular endothelial cells,95 activate iNOS and up-regulate production of NO.96

Fermented soy beans, known as natto, also work to enhance the cardiovascular system. In the 1980s, Hiroyuki Sumi isolated the active ingredient from natto, an enzyme that he named nattokinase. That enzyme could break up fibrin into smaller pieces, and upregulates the plasminogen activation system (PAS), an enzymatic cascade involved in the control of fibrin degradation, matrix turnover and cell invasion.97 Nattokinase decreases blood viscosity without adversely affecting the normal coagulation cascade.98

A recent study out of the University of Southern California, Los Angeles, examined the effects of nattokinase on different blood parameters, and found a significant, dose-dependent decrease of platelet aggregation and low-shear viscosity.99 Japanese researchers induced endothelial damage in the rat femoral artery to examine the effects of natto supplementation prior to and after injury.100 While the femoral arteries reopened in both the natto-treated and control animals within eight hours of injury, the natto suppressed IMT associated with endothelial injury, and showed enhanced thrombolysis near the injury site.

A clinical trial coordinated out of G D’Annunzio University, Pescara, Italy, examined the impact of an oral profibrinolytic supplement (as Flite Tabs, a combination of Pycnogenol and nattokinase) on DVT during long-haul flights.101 A group of 204 subjects at high risk of DVT were randomized to receive the supplement or placebo; after flights, there was an increase in edema in control subjects and a decrease in the intervention group. In addition, the supplement reduced thrombotic events in the subjects.

Another compound used to break down proteins in the body is bromelain, an enzyme isolated from pineapple. Research suggests it may inhibit platelet aggregation and thrombosis with fibrinolytic activity.102,103 In vitro and in vivo work at the Free University of Berlin, Germany, found incubation of platelets with bromelain could prevent thrombin-induced platelet aggregation and reduce platelet adhesion to endothelial cells.104 In addition, bromelain orally dosed at 60 mg/kg could inhibit thrombus formation in a time-dependent manner.

Another specialty compound, milk-derived tripeptides, appears to have positive effects on endothelial-dependent and -independent vasodilation. Researchers from the University of Helsinki, Finland, evaluated the anti-hypertensive mechanisms and vascular effects of tetrapeptides from milk protein in spontaneously hypertensive rats (SHR).105 The tetrapeptides from alpha-lactorphin and beta-lactoglobulin improved vascular relaxation, with the former affecting endothelial function and the latter enhancing endothelium-independent relaxation. The Finnish researchers also reported long-term intake of the peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) in SHR attenuates the development of hypertension by inhibiting angiotension converting enzyme (ACE), a key regulator for the production of the vasoconstricting hormone Angiotensin 2.106 Further, there is evidence from animal trials that the opioid receptors may be involved in the ability of tetrapeptides to lower diastolic and systolic blood pressure.107

Formulators have a broad range of ingredients—and marketers a great opportunity—to address vascular health for long-term wellness. By enhancing the strength of the circulatory system, consumers ensure that there will be blood, where and when they need it throughout the body, and functioning with optimal power. 

Editor's Note: References follow on next page.


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