- Email: [email protected]
Biomechanopharmacology: a new borderline discipline
Update
TRENDS in Pharmacological Sciences
Vol.27 No.6 June 2006
Research Focus
Biomechanopharmacology: a new borderline discipline Fulong Liao1,2, Min Li3, Dong Han4, Jun Cao1 and Keji Chen2 1
Institute of Chinese Materia Medica, China Academy of Traditional Chinese Medicine, Beijing 100700, China National Cardiovascular Centre of Integrated Traditional Chinese and Western Medicine, China–Japan Friendship Hospital, Beijing 100029, China 3 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 4 National Center for Nanoscience and Technology, Beijing 100080, China 2
Flowing blood is more than a drug transporter in pharmacology; its mechanical impact should also be considered. The in vitro pharmacological dose–response pattern of endothelial cellular functions can be significantly modified by in vivo shear stress. A new borderline discipline, biomechanopharmacology, is forming at the boundary between biomechanics and pharmacology. Biomechanopharmacology will probably consist of both the pharmacological intervention of signals induced by biomechanical factors and the biomechanical influence on pharmacokinetics and pharmacodynamics, in addition to the joint effect of biomechanical and pharmacological factors. Recent investigations show that exercise enhances the shear of pulsatile blood flow to stimulate angiogenesis. The benefits of exercise for gaining joint biomechanical and pharmacological effects should be emphasized. Flowing blood and its biomechanical effects More than a century ago, Virchow recognized that blood flow has an important role in thrombosis. During the past two decades, normal endothelial function has been identified as being integral to vascular health. Researchers found that hemodynamic forces can have a crucial role in vascular physiology and pathophysiology. One of the forces acting on blood vessels is shear stress (SS): namely, the friction force between flowing blood and the endothelial cell (EC) surface. The maintenance of physiological laminar SS is crucial for normal vascular functioning, which includes the regulation of vascular diameter – the most influential factor in blood flow volume – and the inhibition of proliferation, thrombosis and inflammation of the vessel wall. Disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. An abnormal flow pattern can promote changes in endothelial gene expression, cytoskeletal arrangement, wound repair and leukocyte adhesion, and affects the vasoreactive, oxidative and inflammatory states of the artery wall [1]. Disturbed SS also influences the site selectivity of atherosclerotic plaque formation and its associated vessel wall remodeling, which can, in turn, affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts [1]. The cerebral vasculature is a Corresponding author: Liao, F. ([email protected]). Available online 6 May 2006
new therapeutic target for treating neurological disorders such as multiple sclerosis and epilepsy, and the severity of Alzheimer’s disease is related to dysfunction of the blood– brain barrier: the crucial role of SS in homeostasis and pathophysiology has been recognized [2]. Flowing blood is more than a transporter and deliverer of oxygen, nutrition, metabolic products and drugs. Its biomechanical impact on ECs should be considered in pharmacology. If SS were a drug, it would be a multitargeted drug. Arterial SS within a physiological range probably induces endothelial quiescence and an atheroprotective gene expression profile. Low SS might stimulate an atherogenic phenotype, whereas high SS might induce a prothrombotic state [3]. The in vivo vascular EC undergoes three types of mechanical force, the intensity of which varies according to the vascular bed: SS (0–6 Pa), hydrostatic pressure (0.4–17.3 kPa) and periodic parietal deformation (0–3 Hz) [4]. Published articles concerning the mechanical effects on ECs deal mainly with SS. The effects of the other types of force require further study. The combined effects of biomechanical and pharmacological factors Mechanical factors are occasionally considered in pharmacology, notably in orthopedics. Cartilage-derived morphogenetic proteins (CDMPs) induce cartilage or bone formation when implanted subcutaneously or intramuscularly in an appropriate carrier. A study analyzing the response to CDMP-2 implants at different sites and under different loading conditions in rat reported an inverse relationship between the amount of bone and the degree of mechanical stimulus [5]. The study indicates that the response to CDMP-2 is dependent on the mechanical situation at the site of CDMP-2 application. As a consequence of knowledge merging, a borderline term – biomechanopharmacology – came into use for the following type of work [6]. Tetramethylparazine (TMP) has been used as an antiplatelet drug in China since the 1970s. Recently, Chinese pharmacologists have been interested in its effect on ECs. The joint effect of TMP and SS on the early apoptosis of rat cerebral microvascular ECs (rCMECs) was investigated by the administration of TMP at different levels of SS generated by rotational cone–plate rheometer [6]. In the absence of stimulation, rCMECs underwent apoptosis in culture (rateZ9.97%). As a single factor, TMP and SS each
www.sciencedirect.com 0165-6147/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2006.04.001
288
Update
TRENDS in Pharmacological Sciences
inhibited apoptosis significantly (for both, P!0.001), following the general pharmacological dose–response pattern. With regard to joint effects, mid-dose combinations of SS and TMP, rather than high-dose combinations, seem to be more effective at lowering the apoptosis of rCMECs (to less than half the non-stimulation level) [6]. This indicates that the orthodox pattern of pharmacological effects could be significantly modified when biomechanical factors that influence endothelial function are involved. In other words, the dose–response relationship might follow a more complicated pattern in biomechanopharmacology. Temozolomide is a strong inhibitor of angiogenesis, the process that leads to the formation of new blood vessels. The actions of this drug involve the induction of EC apoptosis. A flow chamber with independent adjustment for levels of SS and pressure was employed to study the joint influence of SS (0–42 dyne/cm2), pressure (0– 42 mm Hg) and temozolomide (0–350 mmol/L) on the apoptosis of rCMECs. The apoptosis determined by flow cytometer showed that a combination of pressure, SS and temozolomide for eight hours increases the rate of EC apoptosis markedly compared with temozolomide alone (J. Cao, PhD thesis, China Academy of Traditional Chinese Medicine, 2005). This indicates that the effectiveness of a drug can be significantly modified when mechanical factors are also present. Alternatively, a bioresponse induced by biomechanical factors can be disrupted by pharmacological factors. For example, von Willebrand Factor (vWF) secretion by ECs
Vol.27 No.6 June 2006
can be regulated by SS. A recent study showed that TMP and diallyl trisulfide (a compound contained in garlic) have inhibitory effects on the shear-induced vWF secretion of cultured human umbilical vein ECs [7]. Furthermore, tissue-type plasminogen activator (tPA), the potent thrombolytic produced by ECs, can be regulated by medicine that promotes blood circulation. Experimental evidence shows that an ancient herbal prescription comprising herbs for invigorating vital energy and activating blood circulation, buyang huanwu tang, alleviates photochemically induced cerebral infarction in rats by elevating plasma tPA levels [8]. Exercise as a general practice in biomechanopharmacology When pharmacological and mechanical factors are jointly considered for regulating endothelium function, a drug must be taken with a required optimum level of blood SS. An important issue is how to control the level of SS. There are several choices: (i) mechanical measures such as enhanced external counterpulsation (EECP) [9]; (ii) selfregulative measures of exercise; and (iii) a pharmacological measure – the application of promoters of blood circulation. EECP, a noninvasive cardiac assist device for augmenting diastolic blood pressure by electrocardiogram-triggered diastolic inflation and deflation of cuffs wrapped around the lower extremities, has beneficial effects on the treatment of cardiovascular disorders. However, it might not be readily available because of the special equipment that is required for its use. Fortunately,
(a) 6000 Tubule formation (AU)
*
*
5000 *
4000 3000 2000 1000 0
Static
1.4
5.3
13.2
19.8
Flow (dyne/cm2) (b) (i)
(ii)
Figure 1. SS of pulsatile flow increases angiogenesis in a force-dependent manner. (a) After exposure to static conditions (0 dyne/cm2) or pulsatile flow (1.4–19.8 dyne/cm2) for 16 h, angiogenesis of bovine aortic endothelial cells (BAECs) is expressed in arbitrary units (AU) as tubule formation on matrigel. *ZP!0.05 compared with static cultures. (b) Representative image of network formation on matrigel of BAECs maintained under (i) static conditions or (ii) SS conditions (13.2 dyne/cm2) for 16 h. Figure modified, with permission, from Ref. [14]. www.sciencedirect.com
Update
TRENDS in Pharmacological Sciences
the increased blood flow associated with exercise is thought to affect EC function by exerting SS on the endothelial lining of the vessel. There is increasing evidence that exercising regularly and avoiding sedentariness reduce the risk of both arterial and venous thrombosis and that doing so also has systemic antithrombotic and anti-inflammatory effects [10]. Nitric oxide (NO)-dependent vasodilatation and the plasma concentration of NO and cGMP are significantly regulated by exercise and blood SS [11,12]. Angiogenesis has a key role in the growth and function of normal and pathological tissues. Diseases that, not long ago, were considered untreatable are now potential targets for either antiangiogenic therapy (i.e. diabetic retinopathy and endometriosis) or proangiogenic therapy (i.e. ischemic heart disease and diabetic limb rescue) [13]. Experiments indicate that enhanced shear of pulsatile blood flow due to exercise stimulates angiogenesis [14] (Figure 1). At this point, one might be unsure as to how this fits with the ability of SS to promote the effects of antiangiogenic drugs and to promote EC quiescence. In fact, the effects of SS are condition dependent. They vary according to the combination of multifactors, including the form of SS (laminar, pulsatile or turbulence), the amplitude of SS and the joint factors presented, such as the amplitude of blood pressure and the different kinds and doses of drug involved. Future investigations will determine the bioresponsive patterns to various combinations. Exercise could have antihypertensive and antiatherosclerotic effects on the cardiovascular system. It has recently been found that regular exercise can be a fundamental form of therapy for preventing diabetic cardiovascular complications that are potentiated by endothelial dysfunction [15]. We predict that, in the future when writing a prescription, doctors will advise patients to do certain forms and levels of exercise. Concluding remarks and future perspectives Biomechanics is the missing piece in classical pharmacology. Biological responses and biomechanical forces should be jointly applied in pharmacology. On the one hand, biomechanics are currently making great efforts to understand mechanical impacts on cellular functions, especially SS on EC functions. On the other hand, the medical field is becoming more aware of the involvement of SS in vascular biology and pathology. We believe that a new borderline discipline – biomechanopharmacology, a term that came into use in 2002 – is forming at the boundary between biomechanics and pharmacology. Research into the interactions among blood SS, EC secretion and pharmacodynamics is at the frontier of the discipline. It remains to be seen whether endothelial
www.sciencedirect.com
Vol.27 No.6 June 2006
289
protectors and regulators, together with the biomechanical interactive effects of flowing blood, can write a new chapter in pharmacology: biomechanopharmacology. The chapter would probably consist of both the pharmacological interventions on biomechanical factors and the biomechanical influences on pharmacokinetics and pharmacodynamics. The use of exercise should be emphasized for gaining joint biomechanical and pharmacological effects. To benefit from the new discipline, go with a biomechanopharmacologically tailored exercise. Acknowledgements This research was supported in part by grants from Natural Science Foundation of China (10272116 and 90209055), 973 Project (04051J1173) and Faculty Research Grant of Hong Kong Baptist University (03–04/II53 and 03–04/II-26). We appreciate the guidance of Zhengang Wang from Peking Union Medical College.
References 1 Cunningham, K.S. and Gotlieb, A.I. (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab. Invest. 85, 9–23 2 Krizanac-Bengez, L. et al. (2004) The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostasis and pathophysiology. Neurol. Res. 26, 846–853 3 Kazmierski, R. (2003) Biomechanic shear stress in carotid arteries and atherosclerosis development. Postepy Hig. Med. Dosw. 57, 713–725 4 Muller, S. et al. (2004) From hemorheology to vascular mechanobiology: an overview. Clin. Hemorheol. Microcirc. 30, 185–200 5 Forslund, C. and Aspenberg, P. (2002) CDMP-2 induces bone or tendon-like tissue depending on mechanical stimulation. J. Orthop. Res. 20, 1170–1174 6 Liao, F. et al. (2003) The influences of Ligustrazine and shear stress on PS transferring of endothelial cell membrane investigated by evanescent wave exciting. Acta Biophysica Sinica 19, 92–96 7 Liao, F. et al. (2001) Influences of diallyl trisulfide on endothelial secretion of vWF and on platelet aggregation. Nat. Med. J. China 81, 508–509 8 Han, D. et al. (2001) Effect of Buyang Huanwu (BYHW) Tang upon infarction, vessel damage perumbra, fibrinolytic system activity and endothelin. Chinese J. Experimental Traditional Medical Formulae 7, 21–24 9 Shea, M.L. et al. (2005) An update on enhanced external counterpulsation. Clin. Cardiol. 28, 115–118 10 Lowe, G.D. (2003) Virchow’s triad revisited: abnormal flow. Pathophysiol. Haemost. Thromb. 33, 455–457 11 Green, D.J. et al. (2004) Effect of exercise training on endotheliumderived nitric oxide function in humans. J. Physiol. 561, 1–25 12 Johnson, L.R. (2001) Short-term exercise training increases AChinduced relaxation and eNOS protein in porcine pulmonary arteries. J. Appl. Physiol. 90, 1102–1110 13 Polverini, P.J. (2002) Angiogenesis in health and disease: insights into basic mechanisms and therapeutic opportunities. J. Dent. Educ. 66, 962–975 14 Cullen, J.P. et al. (2002) Pulsatile flow-induced angiogenesis – role of Gi subunits. Arterioscler. Thromb. Vasc. Biol. 22, 1610–1616 15 Chakraphan, D. et al. (2005) Attenuation of endothelial dysfunction by exercise training in STZ-induced diabetic rats. Clin. Hemorheol. Microcirc. 32, 217–226
TRENDS in Pharmacological Sciences
Vol.27 No.6 June 2006
Research Focus
Biomechanopharmacology: a new borderline discipline Fulong Liao1,2, Min Li3, Dong Han4, Jun Cao1 and Keji Chen2 1
Institute of Chinese Materia Medica, China Academy of Traditional Chinese Medicine, Beijing 100700, China National Cardiovascular Centre of Integrated Traditional Chinese and Western Medicine, China–Japan Friendship Hospital, Beijing 100029, China 3 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 4 National Center for Nanoscience and Technology, Beijing 100080, China 2
Flowing blood is more than a drug transporter in pharmacology; its mechanical impact should also be considered. The in vitro pharmacological dose–response pattern of endothelial cellular functions can be significantly modified by in vivo shear stress. A new borderline discipline, biomechanopharmacology, is forming at the boundary between biomechanics and pharmacology. Biomechanopharmacology will probably consist of both the pharmacological intervention of signals induced by biomechanical factors and the biomechanical influence on pharmacokinetics and pharmacodynamics, in addition to the joint effect of biomechanical and pharmacological factors. Recent investigations show that exercise enhances the shear of pulsatile blood flow to stimulate angiogenesis. The benefits of exercise for gaining joint biomechanical and pharmacological effects should be emphasized. Flowing blood and its biomechanical effects More than a century ago, Virchow recognized that blood flow has an important role in thrombosis. During the past two decades, normal endothelial function has been identified as being integral to vascular health. Researchers found that hemodynamic forces can have a crucial role in vascular physiology and pathophysiology. One of the forces acting on blood vessels is shear stress (SS): namely, the friction force between flowing blood and the endothelial cell (EC) surface. The maintenance of physiological laminar SS is crucial for normal vascular functioning, which includes the regulation of vascular diameter – the most influential factor in blood flow volume – and the inhibition of proliferation, thrombosis and inflammation of the vessel wall. Disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. An abnormal flow pattern can promote changes in endothelial gene expression, cytoskeletal arrangement, wound repair and leukocyte adhesion, and affects the vasoreactive, oxidative and inflammatory states of the artery wall [1]. Disturbed SS also influences the site selectivity of atherosclerotic plaque formation and its associated vessel wall remodeling, which can, in turn, affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts [1]. The cerebral vasculature is a Corresponding author: Liao, F. ([email protected]). Available online 6 May 2006
new therapeutic target for treating neurological disorders such as multiple sclerosis and epilepsy, and the severity of Alzheimer’s disease is related to dysfunction of the blood– brain barrier: the crucial role of SS in homeostasis and pathophysiology has been recognized [2]. Flowing blood is more than a transporter and deliverer of oxygen, nutrition, metabolic products and drugs. Its biomechanical impact on ECs should be considered in pharmacology. If SS were a drug, it would be a multitargeted drug. Arterial SS within a physiological range probably induces endothelial quiescence and an atheroprotective gene expression profile. Low SS might stimulate an atherogenic phenotype, whereas high SS might induce a prothrombotic state [3]. The in vivo vascular EC undergoes three types of mechanical force, the intensity of which varies according to the vascular bed: SS (0–6 Pa), hydrostatic pressure (0.4–17.3 kPa) and periodic parietal deformation (0–3 Hz) [4]. Published articles concerning the mechanical effects on ECs deal mainly with SS. The effects of the other types of force require further study. The combined effects of biomechanical and pharmacological factors Mechanical factors are occasionally considered in pharmacology, notably in orthopedics. Cartilage-derived morphogenetic proteins (CDMPs) induce cartilage or bone formation when implanted subcutaneously or intramuscularly in an appropriate carrier. A study analyzing the response to CDMP-2 implants at different sites and under different loading conditions in rat reported an inverse relationship between the amount of bone and the degree of mechanical stimulus [5]. The study indicates that the response to CDMP-2 is dependent on the mechanical situation at the site of CDMP-2 application. As a consequence of knowledge merging, a borderline term – biomechanopharmacology – came into use for the following type of work [6]. Tetramethylparazine (TMP) has been used as an antiplatelet drug in China since the 1970s. Recently, Chinese pharmacologists have been interested in its effect on ECs. The joint effect of TMP and SS on the early apoptosis of rat cerebral microvascular ECs (rCMECs) was investigated by the administration of TMP at different levels of SS generated by rotational cone–plate rheometer [6]. In the absence of stimulation, rCMECs underwent apoptosis in culture (rateZ9.97%). As a single factor, TMP and SS each
www.sciencedirect.com 0165-6147/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2006.04.001
288
Update
TRENDS in Pharmacological Sciences
inhibited apoptosis significantly (for both, P!0.001), following the general pharmacological dose–response pattern. With regard to joint effects, mid-dose combinations of SS and TMP, rather than high-dose combinations, seem to be more effective at lowering the apoptosis of rCMECs (to less than half the non-stimulation level) [6]. This indicates that the orthodox pattern of pharmacological effects could be significantly modified when biomechanical factors that influence endothelial function are involved. In other words, the dose–response relationship might follow a more complicated pattern in biomechanopharmacology. Temozolomide is a strong inhibitor of angiogenesis, the process that leads to the formation of new blood vessels. The actions of this drug involve the induction of EC apoptosis. A flow chamber with independent adjustment for levels of SS and pressure was employed to study the joint influence of SS (0–42 dyne/cm2), pressure (0– 42 mm Hg) and temozolomide (0–350 mmol/L) on the apoptosis of rCMECs. The apoptosis determined by flow cytometer showed that a combination of pressure, SS and temozolomide for eight hours increases the rate of EC apoptosis markedly compared with temozolomide alone (J. Cao, PhD thesis, China Academy of Traditional Chinese Medicine, 2005). This indicates that the effectiveness of a drug can be significantly modified when mechanical factors are also present. Alternatively, a bioresponse induced by biomechanical factors can be disrupted by pharmacological factors. For example, von Willebrand Factor (vWF) secretion by ECs
Vol.27 No.6 June 2006
can be regulated by SS. A recent study showed that TMP and diallyl trisulfide (a compound contained in garlic) have inhibitory effects on the shear-induced vWF secretion of cultured human umbilical vein ECs [7]. Furthermore, tissue-type plasminogen activator (tPA), the potent thrombolytic produced by ECs, can be regulated by medicine that promotes blood circulation. Experimental evidence shows that an ancient herbal prescription comprising herbs for invigorating vital energy and activating blood circulation, buyang huanwu tang, alleviates photochemically induced cerebral infarction in rats by elevating plasma tPA levels [8]. Exercise as a general practice in biomechanopharmacology When pharmacological and mechanical factors are jointly considered for regulating endothelium function, a drug must be taken with a required optimum level of blood SS. An important issue is how to control the level of SS. There are several choices: (i) mechanical measures such as enhanced external counterpulsation (EECP) [9]; (ii) selfregulative measures of exercise; and (iii) a pharmacological measure – the application of promoters of blood circulation. EECP, a noninvasive cardiac assist device for augmenting diastolic blood pressure by electrocardiogram-triggered diastolic inflation and deflation of cuffs wrapped around the lower extremities, has beneficial effects on the treatment of cardiovascular disorders. However, it might not be readily available because of the special equipment that is required for its use. Fortunately,
(a) 6000 Tubule formation (AU)
*
*
5000 *
4000 3000 2000 1000 0
Static
1.4
5.3
13.2
19.8
Flow (dyne/cm2) (b) (i)
(ii)
Figure 1. SS of pulsatile flow increases angiogenesis in a force-dependent manner. (a) After exposure to static conditions (0 dyne/cm2) or pulsatile flow (1.4–19.8 dyne/cm2) for 16 h, angiogenesis of bovine aortic endothelial cells (BAECs) is expressed in arbitrary units (AU) as tubule formation on matrigel. *ZP!0.05 compared with static cultures. (b) Representative image of network formation on matrigel of BAECs maintained under (i) static conditions or (ii) SS conditions (13.2 dyne/cm2) for 16 h. Figure modified, with permission, from Ref. [14]. www.sciencedirect.com
Update
TRENDS in Pharmacological Sciences
the increased blood flow associated with exercise is thought to affect EC function by exerting SS on the endothelial lining of the vessel. There is increasing evidence that exercising regularly and avoiding sedentariness reduce the risk of both arterial and venous thrombosis and that doing so also has systemic antithrombotic and anti-inflammatory effects [10]. Nitric oxide (NO)-dependent vasodilatation and the plasma concentration of NO and cGMP are significantly regulated by exercise and blood SS [11,12]. Angiogenesis has a key role in the growth and function of normal and pathological tissues. Diseases that, not long ago, were considered untreatable are now potential targets for either antiangiogenic therapy (i.e. diabetic retinopathy and endometriosis) or proangiogenic therapy (i.e. ischemic heart disease and diabetic limb rescue) [13]. Experiments indicate that enhanced shear of pulsatile blood flow due to exercise stimulates angiogenesis [14] (Figure 1). At this point, one might be unsure as to how this fits with the ability of SS to promote the effects of antiangiogenic drugs and to promote EC quiescence. In fact, the effects of SS are condition dependent. They vary according to the combination of multifactors, including the form of SS (laminar, pulsatile or turbulence), the amplitude of SS and the joint factors presented, such as the amplitude of blood pressure and the different kinds and doses of drug involved. Future investigations will determine the bioresponsive patterns to various combinations. Exercise could have antihypertensive and antiatherosclerotic effects on the cardiovascular system. It has recently been found that regular exercise can be a fundamental form of therapy for preventing diabetic cardiovascular complications that are potentiated by endothelial dysfunction [15]. We predict that, in the future when writing a prescription, doctors will advise patients to do certain forms and levels of exercise. Concluding remarks and future perspectives Biomechanics is the missing piece in classical pharmacology. Biological responses and biomechanical forces should be jointly applied in pharmacology. On the one hand, biomechanics are currently making great efforts to understand mechanical impacts on cellular functions, especially SS on EC functions. On the other hand, the medical field is becoming more aware of the involvement of SS in vascular biology and pathology. We believe that a new borderline discipline – biomechanopharmacology, a term that came into use in 2002 – is forming at the boundary between biomechanics and pharmacology. Research into the interactions among blood SS, EC secretion and pharmacodynamics is at the frontier of the discipline. It remains to be seen whether endothelial
www.sciencedirect.com
Vol.27 No.6 June 2006
289
protectors and regulators, together with the biomechanical interactive effects of flowing blood, can write a new chapter in pharmacology: biomechanopharmacology. The chapter would probably consist of both the pharmacological interventions on biomechanical factors and the biomechanical influences on pharmacokinetics and pharmacodynamics. The use of exercise should be emphasized for gaining joint biomechanical and pharmacological effects. To benefit from the new discipline, go with a biomechanopharmacologically tailored exercise. Acknowledgements This research was supported in part by grants from Natural Science Foundation of China (10272116 and 90209055), 973 Project (04051J1173) and Faculty Research Grant of Hong Kong Baptist University (03–04/II53 and 03–04/II-26). We appreciate the guidance of Zhengang Wang from Peking Union Medical College.
References 1 Cunningham, K.S. and Gotlieb, A.I. (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab. Invest. 85, 9–23 2 Krizanac-Bengez, L. et al. (2004) The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostasis and pathophysiology. Neurol. Res. 26, 846–853 3 Kazmierski, R. (2003) Biomechanic shear stress in carotid arteries and atherosclerosis development. Postepy Hig. Med. Dosw. 57, 713–725 4 Muller, S. et al. (2004) From hemorheology to vascular mechanobiology: an overview. Clin. Hemorheol. Microcirc. 30, 185–200 5 Forslund, C. and Aspenberg, P. (2002) CDMP-2 induces bone or tendon-like tissue depending on mechanical stimulation. J. Orthop. Res. 20, 1170–1174 6 Liao, F. et al. (2003) The influences of Ligustrazine and shear stress on PS transferring of endothelial cell membrane investigated by evanescent wave exciting. Acta Biophysica Sinica 19, 92–96 7 Liao, F. et al. (2001) Influences of diallyl trisulfide on endothelial secretion of vWF and on platelet aggregation. Nat. Med. J. China 81, 508–509 8 Han, D. et al. (2001) Effect of Buyang Huanwu (BYHW) Tang upon infarction, vessel damage perumbra, fibrinolytic system activity and endothelin. Chinese J. Experimental Traditional Medical Formulae 7, 21–24 9 Shea, M.L. et al. (2005) An update on enhanced external counterpulsation. Clin. Cardiol. 28, 115–118 10 Lowe, G.D. (2003) Virchow’s triad revisited: abnormal flow. Pathophysiol. Haemost. Thromb. 33, 455–457 11 Green, D.J. et al. (2004) Effect of exercise training on endotheliumderived nitric oxide function in humans. J. Physiol. 561, 1–25 12 Johnson, L.R. (2001) Short-term exercise training increases AChinduced relaxation and eNOS protein in porcine pulmonary arteries. J. Appl. Physiol. 90, 1102–1110 13 Polverini, P.J. (2002) Angiogenesis in health and disease: insights into basic mechanisms and therapeutic opportunities. J. Dent. Educ. 66, 962–975 14 Cullen, J.P. et al. (2002) Pulsatile flow-induced angiogenesis – role of Gi subunits. Arterioscler. Thromb. Vasc. Biol. 22, 1610–1616 15 Chakraphan, D. et al. (2005) Attenuation of endothelial dysfunction by exercise training in STZ-induced diabetic rats. Clin. Hemorheol. Microcirc. 32, 217–226