ATHEROSCLEROSIS UPDATE 0
ATHEROSCLEROSE: LE POINT Canadian Atherosclerosis Society/Societe canadienne d'atherosclerose
Endothelial cell growth factors in atherogenesis Gayle A. Hoover, ScD P olypeptide growth factors stimulate replication or hypertrophy of target cells' by binding to specific plasma membrane receptors. They may bind to the cells that produce them (autocrine), diffuse to neighbouring target cells (paracrine) or be carried to distal target cells (endocrine).' Endothelial cell growth factors (ECGFs) are a family of related polypeptides originally named according to their tissue of origin or target cells, which include several normal and transformed cell types.2 Their strong affinity for heparin has simplified purification and classification and may be significant in vivo.3 All fall into two structurally related classes, acidic and basic; within each class the growth factors are various molecular weight forms of the same molecule.3 ECGFs are almost ubiquitous in normal tissues and many types of tumours.2 Arterial and capillary endothelial cells (EC), arterial smooth muscle cells (SMC) and stimulated macrophages2 synthesize some form of ECGFs. All ECGFs stimulate cell division in cultures of large-vessel and capillary EC.2 Heparin significantly enhances the mitogenic activity of the acidic form but not the basic.2 Although the effect on EC replication in vivo can only be assumed as yet, high-affinity binding sites have been demonstrated on intact endothelium in vivo.2 ECGFs also stimulate cell division in arterial SMC cultures.2 In-vivo bioassays have demonstrated that ECGFs are potent stimulators of angiogenesis,2,3 presumably acting as an EC chemoattractant as well as stimulating cell division.2 Questions remain about how ECGFs reach their target cells. The apparent lack of a signal peptide required for cellular export may explain why cultured cells fail to secrete the growth factor.2,3 One form of ECGF has been found intracellularly and associated with the matrix of cultured EC, probably
bound to heparan sulfate;3 thus, it may be held in storage for release only when signalled. This would explain how these growth factors can be widely distributed in the body, yet EC turnover is normally very low.3 Conceivably in atherogenesis ECGFs may be released as a result of injury or malfunction of EC to replace damaged cells. The free growth factor could also stimulate SMC replication in underlying intima. Proliferating EC express the gene for another SMC mitogen, whereas intact endothelium does not.4 Quiescent EC secrete a heparin-like substance that inhibits SMC division; multiplying EC do not.5 Macrophages migrating to sites of arterial injury, as well as SMC, may release additional ECGFs. As stimulators of angiogenesis ECGFs could evoke ingrowth of vasa vasorum to sustain the growth of atherosclerotic plaques.6 These may be fragile vessels prone to hemorrhage.6 Therefore, by regulating EC and SMC division and angiogenesis by autocrine and paracrine mechanisms, ECGFs in the arterial wall may be important in atherogenesis.
References 1. James R, Bradshaw RA: Polypeptide growth factors. Annu Rev Biochem 1984; 53: 259-292 2. Burgess WH, Maciag T: The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 1989; 58: 575-606 3. Folkman J, Klagsbrun M: Angiogenic factors. Science 1987; 235: 442-447 4. Barrett TB, Gajdusek CM, Schwartz SM et al: Expression of the sis gene by endothelial cells in culture and in vivo. Proc NatlAcadSci USA 1984; 81: 6772-6774 5. Rosenberg RD, Reilly C, Fritze L: Atherogenic regulation by heparin-like molecules. Ann NYAcad Sci 1985; 454: 270-278 6. Barger AC, Beeukes R, Lainey LL et al: Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl JMed 1984; 310: 175-177
The opinions expressed in this article are those of the author and not necessarily those of the Canadian Atherosclerosis Society.
Reprint requests to: Dr. Gayle A. Hoover, cdo Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste. Catherine Rd., Montreal, PQ H3T IE2 -
For prescribing information see page 1120
CAN MED ASSOC J 1990; 143 (10)
1035
ATHEROSCLEROSE: LE POINT Canadian Atherosclerosis Society/Societe canadienne d'atherosclerose
Endothelial cell growth factors in atherogenesis Gayle A. Hoover, ScD P olypeptide growth factors stimulate replication or hypertrophy of target cells' by binding to specific plasma membrane receptors. They may bind to the cells that produce them (autocrine), diffuse to neighbouring target cells (paracrine) or be carried to distal target cells (endocrine).' Endothelial cell growth factors (ECGFs) are a family of related polypeptides originally named according to their tissue of origin or target cells, which include several normal and transformed cell types.2 Their strong affinity for heparin has simplified purification and classification and may be significant in vivo.3 All fall into two structurally related classes, acidic and basic; within each class the growth factors are various molecular weight forms of the same molecule.3 ECGFs are almost ubiquitous in normal tissues and many types of tumours.2 Arterial and capillary endothelial cells (EC), arterial smooth muscle cells (SMC) and stimulated macrophages2 synthesize some form of ECGFs. All ECGFs stimulate cell division in cultures of large-vessel and capillary EC.2 Heparin significantly enhances the mitogenic activity of the acidic form but not the basic.2 Although the effect on EC replication in vivo can only be assumed as yet, high-affinity binding sites have been demonstrated on intact endothelium in vivo.2 ECGFs also stimulate cell division in arterial SMC cultures.2 In-vivo bioassays have demonstrated that ECGFs are potent stimulators of angiogenesis,2,3 presumably acting as an EC chemoattractant as well as stimulating cell division.2 Questions remain about how ECGFs reach their target cells. The apparent lack of a signal peptide required for cellular export may explain why cultured cells fail to secrete the growth factor.2,3 One form of ECGF has been found intracellularly and associated with the matrix of cultured EC, probably
bound to heparan sulfate;3 thus, it may be held in storage for release only when signalled. This would explain how these growth factors can be widely distributed in the body, yet EC turnover is normally very low.3 Conceivably in atherogenesis ECGFs may be released as a result of injury or malfunction of EC to replace damaged cells. The free growth factor could also stimulate SMC replication in underlying intima. Proliferating EC express the gene for another SMC mitogen, whereas intact endothelium does not.4 Quiescent EC secrete a heparin-like substance that inhibits SMC division; multiplying EC do not.5 Macrophages migrating to sites of arterial injury, as well as SMC, may release additional ECGFs. As stimulators of angiogenesis ECGFs could evoke ingrowth of vasa vasorum to sustain the growth of atherosclerotic plaques.6 These may be fragile vessels prone to hemorrhage.6 Therefore, by regulating EC and SMC division and angiogenesis by autocrine and paracrine mechanisms, ECGFs in the arterial wall may be important in atherogenesis.
References 1. James R, Bradshaw RA: Polypeptide growth factors. Annu Rev Biochem 1984; 53: 259-292 2. Burgess WH, Maciag T: The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 1989; 58: 575-606 3. Folkman J, Klagsbrun M: Angiogenic factors. Science 1987; 235: 442-447 4. Barrett TB, Gajdusek CM, Schwartz SM et al: Expression of the sis gene by endothelial cells in culture and in vivo. Proc NatlAcadSci USA 1984; 81: 6772-6774 5. Rosenberg RD, Reilly C, Fritze L: Atherogenic regulation by heparin-like molecules. Ann NYAcad Sci 1985; 454: 270-278 6. Barger AC, Beeukes R, Lainey LL et al: Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl JMed 1984; 310: 175-177
The opinions expressed in this article are those of the author and not necessarily those of the Canadian Atherosclerosis Society.
Reprint requests to: Dr. Gayle A. Hoover, cdo Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste. Catherine Rd., Montreal, PQ H3T IE2 -
For prescribing information see page 1120
CAN MED ASSOC J 1990; 143 (10)
1035
