Transforming Growth Factor β Signaling, Vascular Remodeling, and Hypertension

Phyllis August, M.D., M.P.H., and Manikkam Suthanthiran, M.D.

The new england journal o f medicine

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. has now brought to center stage a multifunctional cytokine, transforming growth factor β (TGF-β).

TGF-β 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-β, by an enzyme called furin (Fig. 1).

TGF-β is linked to human disease primarily as a promoter of fibrosis; there is extensive evidence that TGF-β is overexpressed in chronic kidney disease. TGF-β 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-β levels and blood pressure, and others have shown an association between polymorphisms in the TGF-β gene and hypertension.

Zacchigna et al. showed that an extracellularmatrix molecule associated with blood vessels, Emilin1, regulates the maturation of TGF-β. 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-β fit into this model of hypertension? Using Xenopus laevis embryos and mammalian cell–culture techniques, Zacchigna et al. showed that Emilin1 inhibits TGF-β signaling by binding to the pro–TGF-β precursor in the extracellular space, thereby preventing its maturation into TGF-β (Fig. 1). Consistent with this mechanism is the observation that TGF-β 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-β. This finding provides support for the notion that a deficiency of Emilin1 increases the blood pressure by increasing the availability of TGF-β.

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-β decreases the blood-vessel diameter, which then causes increased peripheral vascular resistance and hypertension in Emilin1−/− mice. However, it is possiblethat 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-β late in life might help address this possibility. Other models of hypertension are linked to an excess of TGF-β, suggesting that TGF-β mediates damage to the renal parenchyma or vasculature, thereby increasing blood pressure. In some of these models, theantibody-mediated blockade of TGF-β has been shown to reduce blood pressure.

Can drugs that lower TGF-β levels be used to treat essential hypertension? Inhibitors of angiotensin-converting enzyme and antagonists of the angiotensin receptor have been shown to reduce TGF-β production by decreasing the levels of angiotensin II (which stimulates TGF-β); whether this reduction contributes to the antihypertensive effects of the inhibitors remains to be determined. New strategies to modulate the fibrogenic effects of TGF-β 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-β 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-β levels on the kidney, the study of the kidneys in Emilin1−/− mice seems critical to a complete understanding of the relation of TGF-β 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-β and related peptidesfor the individualized management of hypertension. A word of caution is in order, however, whenone is considering approaches to suppress the production of TGF-β: a deficiency of TGF-β may have adverse consequences, such as unmitigated inflammation.