Transforming Growth Factor Signaling, Vascular Remodeling, and Hypertension
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《新英格兰医药杂志》
Hypertension affects more than 1 billion adults worldwide and is the leading cause of preventable death. Despite the plethora of drugs available, the disease is adequately controlled in only about one third of patients. Hormones and vasoactive peptides, like lead actors in a drama, have garnered much attention in the context of the pathogenesis of hypertension. A recent study by Zacchigna et al.1 has now brought to center stage a multifunctional cytokine, transforming growth factor (TGF-).
TGF- is a ubiquitously expressed member of a superfamily of proteins critical to developmental processes. It regulates cell growth and differentiation, inflammation, and immunity. One mechanism by which its activity is regulated is the enzymatic cleavage of its inactive precursor, pro–TGF-, by an enzyme called furin (Figure 1).
Figure 1. TGF- Homeostasis and Health.
TGF- is synthesized by virtually all types of cells, in the form of an inactive homodimeric propeptide, pro–TGF-. A recent study by Zacchigna et al.1 shows that an extracellular molecule, Emilin1, inhibits the enzymatic cleavage of this propeptide by the enzyme furin, thereby interfering with TGF- maturation. After TGF- is cleaved from the propeptide, however, additional downstream events control the extent to which TGF- is available. The small latent complex, composed of TGF- and its latency-associated peptide, and the large latent complex, composed of TGF-, latency-associated peptide, and the latent TGF- binding protein control where and when active TGF- is made available. The matrix glycoprotein thrombospondin-1 binds to the latency-associated peptide, which results in the activation of TGF-, an essential step for the binding of TGF- to its receptors. Plasmin and two members of the integrin family (v6 and v8) also activate the latent complexes of TGF- in the extracellular milieu. An excess as well as a deficiency of TGF- has been linked to disease. Overexpression has been implicated in fibrotic disease of the kidney, liver, and lung, as well as in the progression of cancer and hypertension. Deficiency has been associated with inflammation, autoimmunity, atherosclerosis, cancer, and the impaired healing of wounds.
TGF- is linked to human disease primarily as a promoter of fibrosis; there is extensive evidence that TGF- is overexpressed in chronic kidney disease. TGF- has also been implicated in restenosis after angioplasty, atherosclerosis, angiogenesis, and cardiac fibrosis. The evidence associating it with hypertension has steadily been accruing: our group reported a correlation between serum TGF- levels and blood pressure,2 and others have shown an association between polymorphisms in the TGF- gene and hypertension.3
Zacchigna et al. showed that an extracellular-matrix molecule associated with blood vessels, Emilin1, regulates the maturation of TGF-. The observation that Emilin1 is highly expressed in the mouse cardiovascular system during development prompted the authors to investigate cardiovascular structure and function in mice with a deficiency of the molecule (Emilin1–/– mice). Although the mice were morphologically normal, their blood pressures were significantly greater than those of wild-type mice. The cardiac output, vascular contractility, and stiffness of the blood vessels were similar in the two groups of mice, but blood-vessel diameter was smaller and the rate of proliferation of vascular smooth-muscle cells was lower in the Emilin1–/– mice. These observations suggest that reduced blood-vessel diameter, resulting in increased peripheral vascular resistance, is the cause of hypertension in these animals.
Where does TGF- fit into this model of hypertension? Using Xenopus laevis embryos and mammalian cell–culture techniques, Zacchigna et al. showed that Emilin1 inhibits TGF- signaling by binding to the pro–TGF- precursor in the extracellular space, thereby preventing its maturation into TGF- (Figure 1). Consistent with this mechanism is the observation that TGF- signaling in the vascular tissue is greater in Emilin1–/– mice than in wild-type mice. Furthermore, the vascular abnormalities associated with the deficiency of Emilin1 were not observed in mice that both lacked Emilin1 and had half the normal level of TGF-. This finding provides support for the notion that a deficiency of Emilin1 increases the blood pressure by increasing the availability of TGF-.
These experiments offer a new direction for the investigation of the mechanisms of hypertension in humans and, ultimately, for treatment, although some gaps need to be filled. Zacchigna et al. concluded that an excess of TGF- decreases the blood-vessel diameter, which then causes increased peripheral vascular resistance and hypertension in Emilin1–/– mice. However, it is possible that this decreased diameter represents vascular remodeling and is the consequence, rather than the cause, of hypertension. The development of a conditional mouse knockout model that represses the production of TGF- late in life might help address this possibility. Other models of hypertension are linked to an excess of TGF-, suggesting that TGF- mediates damage to the renal parenchyma or vasculature, thereby increasing blood pressure. In some of these models, the antibody-mediated blockade of TGF- has been shown to reduce blood pressure.4
Can drugs that lower TGF- levels be used to treat essential hypertension? Inhibitors of angiotensin-converting enzyme and antagonists of the angiotensin receptor have been shown to reduce TGF- production by decreasing the levels of angiotensin II (which stimulates TGF-)5; whether this reduction contributes to the antihypertensive effects of the inhibitors remains to be determined. New strategies to modulate the fibrogenic effects of TGF- are being pursued in the hope of preventing the progression of renal disease. Clearly, the hemodynamic effects of such strategies should be studied, as should the possibility that the maturation of TGF- could be modulated by compounds with effects similar to those of Emilin1.
The role of the kidney must be considered in the context of this new finding by Zacchigna et al. Increased peripheral vascular resistance alone, without concomitant changes in sodium excretion, will not lead to sustained hypertension. Thus, we must assume that the reduction in blood-vessel diameter that causes hypertension in the Emilin1–/– mouse also causes the constriction of renal vessels, resulting in increased vascular resistance in the kidney. Such increased resistance would shift the relation between sodium excretion and arterial pressure, so that for any given arterial pressure, less sodium would be excreted and hypertension would be sustained. Given the fibrogenic effect of increased TGF- levels on the kidney, the study of the kidneys in Emilin1–/– mice seems critical to a complete understanding of the relation of TGF- to blood pressure.
The study by Zacchigna et al. underscores the power of mechanistic studies to address complex traits such as hypertension. It has opened the door to the exploration of TGF- and related peptides for the individualized management of hypertension. A word of caution is in order, however, when one is considering approaches to suppress the production of TGF-: a deficiency of TGF- may have adverse consequences, such as unmitigated inflammation.
No potential conflict of interest relevant to this article was reported.
Source Information
From Weill Medical College of Cornell University, New York (P.A., M.S.), and the Theresa and Eugene Lang Center for Research and Education, New York Hospital Queens, Flushing (P.A.).
References
Zacchigna L, Vecchione C, Notte A, et al. Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 2006;124:929-942.
Suthanthiran M, Li B, Song JO, et al. Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A 2000;97:3479-3484.
Cambien F, Ricard S, Troesch A, et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. Hypertension 1996;28:881-887.
Lavoie P, Robitaille G, Agharazii M, Ledbetter S, Lebel M, Lariviere R. Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats. J Hypertens 2005;23:1895-1903.
Border WA, Noble NA. Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 1998;31:181-188.(Phyllis August, M.D., M.P)
TGF- is a ubiquitously expressed member of a superfamily of proteins critical to developmental processes. It regulates cell growth and differentiation, inflammation, and immunity. One mechanism by which its activity is regulated is the enzymatic cleavage of its inactive precursor, pro–TGF-, by an enzyme called furin (Figure 1).
Figure 1. TGF- Homeostasis and Health.
TGF- is synthesized by virtually all types of cells, in the form of an inactive homodimeric propeptide, pro–TGF-. A recent study by Zacchigna et al.1 shows that an extracellular molecule, Emilin1, inhibits the enzymatic cleavage of this propeptide by the enzyme furin, thereby interfering with TGF- maturation. After TGF- is cleaved from the propeptide, however, additional downstream events control the extent to which TGF- is available. The small latent complex, composed of TGF- and its latency-associated peptide, and the large latent complex, composed of TGF-, latency-associated peptide, and the latent TGF- binding protein control where and when active TGF- is made available. The matrix glycoprotein thrombospondin-1 binds to the latency-associated peptide, which results in the activation of TGF-, an essential step for the binding of TGF- to its receptors. Plasmin and two members of the integrin family (v6 and v8) also activate the latent complexes of TGF- in the extracellular milieu. An excess as well as a deficiency of TGF- has been linked to disease. Overexpression has been implicated in fibrotic disease of the kidney, liver, and lung, as well as in the progression of cancer and hypertension. Deficiency has been associated with inflammation, autoimmunity, atherosclerosis, cancer, and the impaired healing of wounds.
TGF- is linked to human disease primarily as a promoter of fibrosis; there is extensive evidence that TGF- is overexpressed in chronic kidney disease. TGF- has also been implicated in restenosis after angioplasty, atherosclerosis, angiogenesis, and cardiac fibrosis. The evidence associating it with hypertension has steadily been accruing: our group reported a correlation between serum TGF- levels and blood pressure,2 and others have shown an association between polymorphisms in the TGF- gene and hypertension.3
Zacchigna et al. showed that an extracellular-matrix molecule associated with blood vessels, Emilin1, regulates the maturation of TGF-. The observation that Emilin1 is highly expressed in the mouse cardiovascular system during development prompted the authors to investigate cardiovascular structure and function in mice with a deficiency of the molecule (Emilin1–/– mice). Although the mice were morphologically normal, their blood pressures were significantly greater than those of wild-type mice. The cardiac output, vascular contractility, and stiffness of the blood vessels were similar in the two groups of mice, but blood-vessel diameter was smaller and the rate of proliferation of vascular smooth-muscle cells was lower in the Emilin1–/– mice. These observations suggest that reduced blood-vessel diameter, resulting in increased peripheral vascular resistance, is the cause of hypertension in these animals.
Where does TGF- fit into this model of hypertension? Using Xenopus laevis embryos and mammalian cell–culture techniques, Zacchigna et al. showed that Emilin1 inhibits TGF- signaling by binding to the pro–TGF- precursor in the extracellular space, thereby preventing its maturation into TGF- (Figure 1). Consistent with this mechanism is the observation that TGF- signaling in the vascular tissue is greater in Emilin1–/– mice than in wild-type mice. Furthermore, the vascular abnormalities associated with the deficiency of Emilin1 were not observed in mice that both lacked Emilin1 and had half the normal level of TGF-. This finding provides support for the notion that a deficiency of Emilin1 increases the blood pressure by increasing the availability of TGF-.
These experiments offer a new direction for the investigation of the mechanisms of hypertension in humans and, ultimately, for treatment, although some gaps need to be filled. Zacchigna et al. concluded that an excess of TGF- decreases the blood-vessel diameter, which then causes increased peripheral vascular resistance and hypertension in Emilin1–/– mice. However, it is possible that this decreased diameter represents vascular remodeling and is the consequence, rather than the cause, of hypertension. The development of a conditional mouse knockout model that represses the production of TGF- late in life might help address this possibility. Other models of hypertension are linked to an excess of TGF-, suggesting that TGF- mediates damage to the renal parenchyma or vasculature, thereby increasing blood pressure. In some of these models, the antibody-mediated blockade of TGF- has been shown to reduce blood pressure.4
Can drugs that lower TGF- levels be used to treat essential hypertension? Inhibitors of angiotensin-converting enzyme and antagonists of the angiotensin receptor have been shown to reduce TGF- production by decreasing the levels of angiotensin II (which stimulates TGF-)5; whether this reduction contributes to the antihypertensive effects of the inhibitors remains to be determined. New strategies to modulate the fibrogenic effects of TGF- are being pursued in the hope of preventing the progression of renal disease. Clearly, the hemodynamic effects of such strategies should be studied, as should the possibility that the maturation of TGF- could be modulated by compounds with effects similar to those of Emilin1.
The role of the kidney must be considered in the context of this new finding by Zacchigna et al. Increased peripheral vascular resistance alone, without concomitant changes in sodium excretion, will not lead to sustained hypertension. Thus, we must assume that the reduction in blood-vessel diameter that causes hypertension in the Emilin1–/– mouse also causes the constriction of renal vessels, resulting in increased vascular resistance in the kidney. Such increased resistance would shift the relation between sodium excretion and arterial pressure, so that for any given arterial pressure, less sodium would be excreted and hypertension would be sustained. Given the fibrogenic effect of increased TGF- levels on the kidney, the study of the kidneys in Emilin1–/– mice seems critical to a complete understanding of the relation of TGF- to blood pressure.
The study by Zacchigna et al. underscores the power of mechanistic studies to address complex traits such as hypertension. It has opened the door to the exploration of TGF- and related peptides for the individualized management of hypertension. A word of caution is in order, however, when one is considering approaches to suppress the production of TGF-: a deficiency of TGF- may have adverse consequences, such as unmitigated inflammation.
No potential conflict of interest relevant to this article was reported.
Source Information
From Weill Medical College of Cornell University, New York (P.A., M.S.), and the Theresa and Eugene Lang Center for Research and Education, New York Hospital Queens, Flushing (P.A.).
References
Zacchigna L, Vecchione C, Notte A, et al. Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 2006;124:929-942.
Suthanthiran M, Li B, Song JO, et al. Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A 2000;97:3479-3484.
Cambien F, Ricard S, Troesch A, et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. Hypertension 1996;28:881-887.
Lavoie P, Robitaille G, Agharazii M, Ledbetter S, Lebel M, Lariviere R. Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats. J Hypertens 2005;23:1895-1903.
Border WA, Noble NA. Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 1998;31:181-188.(Phyllis August, M.D., M.P)