↑NO

↑NO

NO

eNOS

L-arginineO2

NADPH

Lumen

↑NO

BH4

Subendothelial Space

Mitochondria

Shear StressInsulinAcetylcholine

PI-3 kinase

Vasodilation

Anti-AdhesionAnti-CoagulationAnti- Fibrolysis

↓NO

NO

eNOS

L-arginineO2

NADPH

Lumen

↓NO

BH4

Subendothelial Space

O2-

ONOO-

O2-

Anti-AdhesionAnti- CoagulationAnti- Fibrolysis

Vasodilation

Ross, R. Atherosclerosis - An inflammatory disease. New England Journal of Medicine 340:115-126, 1999

VASODILATION

Shear Stress

PI-3-Kinase

OxygenL-ArginineNADPH

NitricOxide

eNOS

Cofactors

NO

i

cGMP

↓Ca++

ARTERIAL HEALTH

Flow-Mediated Dilation = 8%

PrePre Post

4.1 mm 4.7 mm

Series10123456789

10

HealthyAgingHeart DiseaseVisceral FatDiabetesHypertensionFM

D (%

)

Faulx, et al, American Heart Journal 145:943-951, 2003

Iiyama, et al. American Heart Journal 132:779-782, 1996

Hashimoto, et al. International Journal of Obesity: Relar Metab Disord 22:477-484, 1998.

Caballero, A.E., Obesity Research 11:1278-1289, 2003.

Celermajer,et al. J Am Coll Cardiol 24:471-476, 1994.

02468

1012141618

FMD (%)MenWomenChildren

Hasimoto, et al. Circulation 92:3431-3435, 1995.

Apparently Healthy

02468

1012

FMD (%) Normal WeightObese

Woo, et al, International Journal of Obesity 28:852-857, 2004

Children

0

2

4

6

8

10

12

20 30 40 50 60 65 70

Years

FMD (%)MenWomen

Celermajer,et al. J Am Coll Cardiol 24:471-476, 1994.

Aging

0123456789

FMD (%)Normal SubcutaneuousVisceral Fat

Hashimoto, et al. International Journal of Obesity: Relar Metab Disord 22:477-484, 1998.

Overweight & Obesity

0

5

10

15

20

Normal BloodPressureHigh BloodPressure

Iiyama, et al. American Heart Journal 132:779-782, 1996

Hypertension

02468

101214

FMD (%)

Normal

GlucoseIntoleranceDiabetes

Caballero, A.E., Obesity Research 11:1278-1289, 2003.

Diabetes

NOL-arginineO2

NADPH

↓NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine

Anti-AdhesionAnti-CoagulationAnti- Fibrolysis

Vasoconstriction

Oxidative Stress

O2-

↓NO

ONOO-

O2-

Non-Smokers Current Smokers Past Smokers0

2

4

6

8

10

12FM

D (%

)

Celemajer, D, et al Circulation 88:2149-2155, 1999

Endothelial Function of Smokers

Non-Smokers

1-4 yrs 5-8 yrs 10-19 yrs >20 yrs0

2

4

6

8

10

12FM

D (%

)

Celemajer, D, et al Circulation 88:2149-2155, 1999

Endothelial Function of Smokers

0

100

200

300

400

500

600

NonobeseGynoid ObesityAndriod Obesity

8 PG

F2al

pha

(pg/

ml)

OXIDATIVE STRESS IN OBESITY

Davi, et al. JAMA 288:2008-2014, 2002

Non Obese Obese0

0.5

1

1.5

2

2.5

3

3.5

PrePost

Lipi

d Hy

drop

erox

ides

(nm

ol/m

l)*

OXIDATIVE STRESS FOLLOWING MAXIMAL EXERCISE

Vincent, et al. Med Sci Sport Sci, 37:213-219, 2005.

0123456789

10

Pre-Meal Post-Meal

Brac

hial

Arte

ry F

MD

(%)

HealthyHealthyDiabetes

Tsai, et al. Clinical Science 106:315-319, 2004Anderson, et al, Atherosclerosis 154:475-483, 2001Ceriello, et al, Circulation 106:1211-1218, 2002

0

1

2

3

4

5

6

7

8

9

10

Series 1

FMD

(%)

0

1

2

3

4

5

6

7

8

9

10

Series 1

FMD

(%)

NOL-arginineO2

NADPH

Lumen

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine ↓NO

↓NO

Anti-AdhesionAnti-CoagulationAnti- Fibrolysis

Vasoconstriction

02468

101214

FMD (%)O

W

Ob

Chl

d

Met

Syn

d

Dia

bete

s

Hea

rt D

is

Pre-TrainingPost-Training

Hamby et al, Diabetes Care 26:2119-2125, 2003Watts, et al, Journal Pediatrics 144:620-625, 2004Walsh, et al, JAP 95:20-25, 2003

EXERCISE IMPROVES ENDOTHELIAL FUNCTION

VASODILATION

i

Before After0

10

20

30

40

50

60

NO

(um

ol/L

)

Maeda, et al. Life Sciences 69:1005-1016, 2001

Eight weeks of training in healthy adults

0

2

4

6

8

10

12

Before After

Arte

rial H

ealth

(FM

D) High Fat

Low Fat

HFM &Exercise

Padilla, et al., European Journal of Applied Physiology, 98:256-262, 2006

0

2

4

6

8

10

12

Pre-Meal Post-Meal

FMD

(%)

InactiveActive

Padilla, et al. Medicine and Science in Sport and Exercise, in press.

7.47.67.8

88.28.48.68.8

99.29.4

Pre-Meal Post-Meal

SOD

Activ

ity

InactiveActive

Fly, et al. Medicine and Science in Sport and Exercise, in press.

3

4

5

6

7

8

9

Baseline Post Exercise

FMD (%)SedentaryActive

Harris, et al, Obesity, 2008

Active & Inactive

Overweight MenFMD

ResponseTreadmillExercise

Oxidative Source

Oxidative Stress( 8 PG F2alpha)

Endothelial Function

Single Physical Activity Session

NO bioavailability Blood Flow

Anti-inflammatory

Myokine( IL-6)

Inflammatory Stress( TNF-alpha)

Antioxidant Defense(SOD)

Insulin Resistance

Visceral Fat ( TNF-alpha)

SystemicInflammation

( CRP)

Habitual Physical Activity

Insulin Resistance