Hertfortshire, England

The birth and death records of nearly 16,000 individuals born

showed that death rates from Cardiovascular disease (CVD) fell

progressively between the low and high birth weight groups.

Osmond C, Barker DJP, Winter PD, Fall CHD, Simmonds J. Early growth and death from cardiovascular disease in women. BMJ 1993;307: 1519-24.

Sheffield, England

Standardized mortality ratios for CVD fell from 119 in men who

weighed 5.5 pounds or less at birth to 74 in men who weighed

more than 8.5 pounds.

Barker DJP, Osmond C, Simmonds SJ, Wield GA. The relation of small head

circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ 1993; 306:422-6

In India,

Among 517 men and women, low birth weight, short

birth length, and small head circumference at birth

were associated with a raised prevalence of CVD.

Stein CE, Fall CHD, Kumaran K, Osmond C, Cox V, Barker DJP. Fetal growth and coronary heart disease in South India. Lancet 1996;348:1478-80.

Intrauterine programming of coronary

heart disease and stroke.

Barker DJ, Acta Paediatr Suppl 1997; 423: 178-182

The fetal origins of coronary heart disease

and non-insulin dependent diabetes in

India. Fall, C.H., and Barker, D.J. Indian Pediatr 1997; 34, 5-8.

Impaired fetal growth and atherosclerosis of

carotid and peripheral arteries.

Martyn CN, Gale CR, Jespersen S, Sherriff SB. Lancet 1998; 352(9123):

173-178. Barker DJ, Clark PM. Rev Reprod 1997; 2(2): 105-112

The fetal origins of hypertension.

Barker DJ, Martyn CN. Adv Nephrol Necker Hosp 1997; 26: 65-72.

Swedish study of 149,378 boys showed that

systolic blood pressure fell by 0.8 mmHg for

every 1 kg increase in birth weight

Nilsson, P.M., Ostergren, P.O., Nyberg, P., Soderstrom, M., and Allebeck,

P. (1997). J Hypertens 15, 1627-1631.

A review of 80 studies of the relationship

between systolic blood pressure and birth

weight in 444,000 males and females of

various races, aged 0-84 years, found that

blood pressure fell approximately 2 mmHg/kg

with increasing birth weight

Huxley, R.R., Shiell, A.W., and Law, C.M. (2000). J Hypertens 18, 815-831.

The process whereby a stimulus at a

critical period of the development leads

to persistent changes in structure,

physiology and metabolism

physiological and molecular mechanisms

which lead to fetal “programming” of

the cardiovascular system are unknown

Impaired synthesis of elastin in the walls of

the aorta and large conduit arteries during

early development may be an initiating

event in the pathogenesis of systemic

hypertension.

Lancet 1997; 350: 953-955.

Berry, C.L., Looker, T., and Germain, J. (1972). The growth and development of the rat aorta. I. Morphological aspects. J Anat 113, 1-16.

the elastin : collagen ratio

in the rabbit aorta = the pulmonary artery

By the age of 2 months,

pulmonary pressure 15 mmHg

systemic blood pressure 40-80 mmHg

the elastin : collagen ratio in the aorta is > in the pulmonary artery

1.75 times

At birth,

Leung DYM, Glagov S, Mathews MB. A new in vitro system for studying cell response to

mechanical stimulation. Different effects of cyclic stretching and agitation on smooth muscle cell biosynthesis. Exp Cell Res 1977; 109: 285-298.

Avolio A, et.al., Quantification of alterations in structure and function of elastin in the arterial media. Hypertension 1998, 32:170-175.

A B

A) a 15-year-old tiger(505 million cycles)

B) a 15-year-old jaguarundi(1025 million cycles)

Izzo, J.L., Jr., and Shykoff, B.E. (2001). Arterial stiffness: clinical relevance,

measurement, and treatment. Rev Cardiovasc Med 2, 29-34, 37-40.

0.2

0.5

0.7

1.0

1.2

1.5

Ep (Nm-2 x 105)

0 50 100 150 200 250

Pressure (mmH)

In rats aged 4

weeks, whose

mothers were fed

a low-protein diet

during pregnancy

show that their

aortas are stiffer

than controls

born to mothers fed a normal diet

Functional stiffness (Ep)

The values of functional elastic modulus

Material stiffness (Einc)

The circumferential incremental elastic modulus

R

PRE p

Rh

PREinc

75.0

The aim of this study was to test the

hypothesis that the impairment of elastin

synthesis during a critical period of blood

vessel development, which leads to

permanent changes in arterial

mechanical properties, may be a

mechanism for the association between

growth restriction in utero, raised arterial stiffness in adulthood.

Female Wistar rats were fed a diet containing 9% casein two weeks before mating, throughout their pregnancy and during weaning for 3 weeks.

An isocaloric diet containing 18% casein was fed to a similar number of pregnant rats

[Langley-Evans et al., 1994] ; both diets were obtained from Hoppe Farms, Woerden, Netherlands

The offspring (8 Males & 8 Females/ diet group (LP, NP)/ aged group)

4, 6, 8, 12, 20, 50 weeks of age

Were sacrificed

Arterial elasticity measurement

0

1

2

3

4

5

6

7

Female Male

Bir

th

weig

ht [

g]

LP group NP group

** **

0

100

200

300

400

500

600

700

800

0 50 100 150 200 250 300 350 400

Age [days]

Bo

dy w

eig

ht

[g]

Female [LP] Female [NP] Male [LP] Male [NP]

Abdominal aorta at 4 weeks of age

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 50 100 150 200 250 300

Pressure (mmHg)

Fu

ncti

on

al m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Abdominal aorta at 50 weeks of age

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 50 100 150 200 250 300

Pressure (mmHg)

Fu

ncti

on

al m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Thoracic aorta at 4 weeks of age

0

0.1

0.2

0.3

0.4

0.5

0.6

0 50 100 150 200 250 300

Pressure (mmHg)

Fu

ncti

on

al m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Thoracic aorta at 50 weeks of age

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 50 100 150 200 250 300

Pressure (mmHg)

Fu

ncti

on

al m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Abdominal aorta

20

40

60

80

100

120

140

0 10 20 30 40 50 60

Age [weeks]

Ep

[N

m-2 x

10

3]

Female [LP] Female [NP] Male [LP] Male [NP]

Thoracic aorta

20

30

40

50

60

70

80

0 10 20 30 40 50 60

Age [weeks]

Ep

[N

m-2 x

10

3]

Female [LP] Female [NP] Male [LP] Male [NP]

Abdominal aorta at 4 weeks of age

0

1

2

3

4

5

6

7

1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9

Relative radius

Incre

men

tal m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Abdominal aorta at 50 weeks of age

0

1

2

3

4

5

6

7

1 1.2 1.4 1.6 1.8 2 2.2

Relative radiusIn

cre

men

tal m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Thoracic aorta at 4 weeks of age

0

1

2

3

4

5

6

1 1.2 1.4 1.6 1.8 2

Relative radius

Increm

en

tal m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Thoracic aorta at 50 weeks of age

0

1

2

3

4

5

6

7

8

1 1.2 1.4 1.6 1.8 2 2.2 2.4

Relative radius

Incre

men

tal m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Abdominal aorta

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 10 20 30 40 50 60

Age [weeks]

Incre

men

tal m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

Thoracic aorta

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60

Age [weeks]

Incre

men

tal m

od

ulu

s (

Nm

-2 x

10

6)

Female [LP] Female [NP] Male [LP] Male [NP]

The results showed that offspring

whose mothers were fed a low protein

diet had lower birthweight than their control counterparts whose mothers were fed a normal protein diet

The functional stiffness of the thoracic

aorta in LP animals (after puberty) was greater than that of controls whereas the

material stiffness was not much affected by growth restriction. The changes in

stiffness with age were similar in LP and

NP animals with a decrease in both

structural and functional stiffness between the ages of 4 and 20 weeks.

The elasticity data obtained to

date does not support the

hypothesis that growth restriction

causes impairment of elastin

synthesis leading to increased

stiffness of the walls of the elastic arteries

Zambian children aged 5-9:

› it was found that those with the lowest birth

weight do indeed have higher systolic

pressure and stiffer femoral arteries than

those with the highest birth weights

Mutiti A, Kelly MP, Greenwald SE. Nutritional status and arterial stiffness in Zambian

children. 4th International Congress of the African Association of Physiological Science, Tetouan, Morocco; 2004

Skilton et al. reported that newborn

human babies with IUGR had a thicker

aortic wall than normal

Skilton, M.R., Evans, N., Griffiths, K.A., Harmer, J.A., and Celermajer, D.S. (2005). Aorticwall thickness in newborns with intrauterine growth restriction. Lancet 365, 1484-1486.

It is commonly agreed that the control of

blood pressure is mediated and influenced

by multiple structural, neural, endocrine,

and renal mechanisms.

As well as mechanisms in which

programming lifelong cardiovascular

function may act together or

independently. Thus, perturbations in

one control mechanism inevitably

lead to compensatory changes in

others and dissecting out those which are primary is likely to be difficult

• Professor SE Greenwald

• Professor Jo Martin

• ICMS staff (Pathology group):

Alex Brown, Carol Nickols, and Chris

Evagora

• Dr. Upa Kukongviriyapan and

• Saowanee Luangaram

• BSc students; Pira Saravanamuthu,

Dominic Greenyer, and Madiha Ahmed

• Thai government.

• Anatomy, KKU staff

• My family