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Editorial: Parathyroid Hormone-Related Protein in Cardiovascular Development and Blood Pressure Regulation

Renovascular Physiology and Pharmacology (INSERM-MENRT) University Louis Pasteur School of Medicine 67085 Strasbourg, France

Address all correspondence and requests for reprints to: Jean-Jacques Helwig, Ph.D., Laboratoire de Physiologie et de Pharmacologie (CJF INSERM 9409, EA MENRT 2307), 11 rue Humann, 67085 Strasbourg Cedex, France. E-mail: jean-jacques.helwig{at}pharmaco-ulp.u-strasbg.fr

	Introduction

Top Introduction References

 
PTH-related protein (PTHrP) was isolated in 1987 as the tumoral factor responsible for the humoral hypercalcemia of malignancy (reviewed in Ref. 1). PTHrP is produced not only by many tumors, but also by virtually all normal cells and tissue types throughout the body during development and adult life. PTHrP and PTH/PTHrP receptor (PTH-R) are present in smooth muscle-rich organs such as bladder, uterus, stomach, intestine, and the chicken oviduct, as well as throughout the cardiovascular system. In the latter system, PTHrP and the PTH-R are produced in the heart as well as in vascular smooth muscle (VSM) and in endothelial cells of all vessels examined so far. Lessons from PTHrP or PTH-R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal development (2). The PTHrP and PTH genes arise from a common ancestral gene. The PTHrP pre-messenger RNA is alternatively spliced to give rise to three initial translation products of 139, 141, and 173 amino acids, depending on the cell type and the species. These forms are in turn posttranslationally processed to form a family of mature peptides, of which PTHrP (1–36) (structurally and functionally related to PTH), PTHrP (38–94) and PTHrP (107–139) are the major secretory forms. Receptors for mid-region and carboxy-terminal PTHrP species have only been defined by indirect pharmacological tools and are still under investigation. On the other hand, the PTH-R, which recognizes PTHrP (1–36) as well as PTH, has been cloned and well characterized in terms of structure, localization, pharmacological properties, and physiological regulation. The PTH-R is an heptahelical, G protein-coupled receptor that binds PTH as well as all of the amino-terminal containing PTHrP species.

Over the last decade, a growing number of studies have provided clear evidence for PTHrP as a novel class of multifunctional peptides. First, PTHrP is a regulator of transepithelial calcium transport in renal tubules, placenta, and possibly the mammary gland. Second, PTHrP is a regulator of development, growth, and differentiation in all tissues that have been examined so far. Finally, PTHrP is a potent regulator of smooth muscle. This latter area has been extensively studied, and PTHrP is now appreciated to be involved in the control of vascular tone as a vasodilator, as well as of cardiac functions as a positive chronotropic and inotropic factor. The PTHrP gene has often been compared with an early gene. This has been proven to be true in smooth muscle where PTHrP expression is quickly and transiently up-regulated by mechanical forces, by vasoconstrictors such as angiotensin II, and growth factors (for complete reviews, see Refs. 3, 4, 5, 6, 7). In two papers appearing in the present issue of Endocrinology, Clemens and co-workers (8, 9) describe for the first time a cardiovascular phenotype of transgenic mice overexpressing PTHrP and/or PTH-R in smooth muscle. These studies not only strongly support PTHrP as a cardiovascular regulatory peptide but also raise a number of intriguing questions concerning the role of PTHrP during the development of the cardiovascular system and the mechanisms by which PTHrP modulates blood pressure in adult animals.

While the expression of PTHrP and PTH-R are known to be spatially and temporally regulated during development of various organs such as bone, skin, mammary gland, or kidney (2, 3, 4, 5, 6, 7), no clear evidence has been obtained to date for a role of PTHrP in the development of the cardiovascular system. In the PTHrP knockout mouse, which dies at birth from a severe skeletal disorder, the cardiovascular system appears to develop normally, suggesting that PTHrP is not an essential factor for the development of the cardiovascular system (2). However, accurate vascular morphometric investigations, such as vessel lumen-to-wall ratio measurements, have not been specifically performed in these mice, and no cardiovascular functional data are available. Massfelder et al. (10) have recently demonstrated that introduction of PTHrP into A10 VSM cells by gene transfer stimulates proliferation of these cells by transport of PTHrP into the nucleus. Paradoxically, the opposite occurred with the addition of exogenous PTHrP: in this setting, PTHrP was antimitogenic. Moreover, the number of dividing cells in the aortic media of PTHrP knockout fetuses was reduced compared with their normal littermates. These studies demonstrate that, in VSM, PTHrP can operate in both a paracrine or autocrine pathway but may also operate via an "intracrine" (nuclear targeting) pathway. PTHrP could thus be involved in both paracrine as well as intracrine signaling pathways of VSM proliferation during angiogenesis and vasculogenesis. The coordinated distribution of PTHrP and PTH-R between adjacent cell types in a wide variety of fetal sites, including bone, kidney, skin, and mammary gland (3, 4, 5, 6, 7), strongly suggests that PTHrP and the PTH-R are involved in the modulation of cell differentiation. Similarly, because PTHrP and PTH-R are present in both VSM cells and endothelial cells, it appears also likely that PTHrP could be involved in the modulation of angiogenesis and vasculogenesis through paracrine signaling pathways.

It is now accepted that continuous exposure of the PTH-R to ligand (PTH or PTHrP) leads to receptor desensitization (11). As discussed below, the PTH-R is rapidly desensitized in vascular tissue in response to sustained exposure to PTHrP or down-regulated in pathological situations in which PTHrP is overexpressed, such as vascular restenosis after angioplasty (12) or hypertension (13). It might therefore be anticipated that PTHrP overexpression in VSM during development would lead to hyperplasia of the cardiovascular system with limited effect on vascular morphogenesis. In the present issue of Endocrinology, Maeda et al. (8) report that, in the aorta of transgenic mice overexpressing PTHrP in VSM, the PTH-R is indeed desensitized without any morphologic abnormalities. This finding strongly suggests that normal vascular development is not perturbed by an excess of endogenous PTHrP, owing to the desensitization of the PTH-R. In turn, this finding also implies that overexpression of PTHrP does not necessarily lead to an increase in PTHrP transport into the nucleus and, in turn, to hyperplasic VSM cells. On the other hand, the possibility that the threshold level of PTHrP overexpression in VSM cells required to induce its mitogenic effect might not have been reached in these transgenic animals cannot be ruled out.

That cardiovascular PTH-R are most likely implicated in differentiating processes during fetal life is further documented in the companion paper in which Qian et al. (9) examined double transgenic mice overexpressing both PTHrP and PTH-R. When the desensitization of vascular PTH-R in PTHrP overexpressing transgenic mice is "overwhelmed" by simultaneous overexpression of both ligand and receptor, the animals died at approximately day 9 of gestational life, apparently from cardiac development abnormalities. In contrast, transgenic mice overexpressing only the PTH-R developed normally, probably because an insufficient level of receptor activation was achieved. While the exact role of PTHrP during early development of the cardiovascular system remains unclear, the papers of Clemens and co-workers (8, 9) provide new and important findings that speak for a role of PTHrP in the cardiac development and differentiation.

While the vasodilatory actions of PTH were already described in the 1920s, the physiological implications of this observation were never clear. With the discovery of PTHrP in the 1980s, the demonstration that PTHrP is normally present in the vascular wall, the demonstration that PTHrP is a potent vasodilator, and that PTH and PTHrP induce vasodilation via the PTH-R, it is now clear that PTHrP is the endogenous vasodilatory ligand (see Refs. 4, 5, 14, 15, 16 for reviews). However, none of these studies answered to the key question as to whether endogenous PTHrP produced by the vascular cells has a significant, long term in vivo regulatory impact on vascular tone and regional hemodynamics. In this context, the reports of Clemens and co-workers (8, 9) elegantly provide convincing preliminary evidence that PTHrP, endogenously produced by the smooth muscle, alters blood pressure homeostasis in conscious animals. Indeed, both transgenic mice lines, overexpressing PTHrP or its receptor in smooth muscle, are hypotensive despite the numerous compensatory mechanisms that would be expected to blunt such a phenotype. This latter idea is reinforced by the fact that blood pressure is lowered despite the concomitant desensitization or down-regulation of the nitric oxide (NO)/cGMP system, discussed below, which seems to occur in mice overexpressing PTHrP.

From a general point of view, desensitization of cellular responsiveness to extracellular ligands is a common phenomenon enabling end functions to adapt to sustained exposure to hormonal stimuli. The mechanisms of homologous desensitization of G-coupled receptors are variable and may include down-regulation of expression, phosphorylation by protein kinases, loss of coupling with distal transductor/effector systems, internalization, and sequestration (17). An important aspect of the vasoactive properties of PTHrP is the strong and dynamic susceptibility of the vascular PTH-R to undergo rapid and transient homologous desensitization in a broad array of in vivo and in vitro vascular beds (11). For instance, a 5-min exposure of rabbit renal vessels to only 10 pM PTHrP (1–34), a concentration that did not affect renal tone, reduced by 25% subsequent vasodilation induced by 100 nM of PTHrP (18). Depending on the cell type, a number of mechanisms have been evoked for the desensitization of the PTH-R, including receptor phosphorylation by protein kinase A or C. In embryonic kidney, 293 cells however, phosphorylation of the stably transfected PTH-R was not blocked by either PKC or PKA inhibitors, suggesting the involvement of other kinase(s) (19). In support of this, the activation of ßARK-1 (ß-adrenergic receptor-kinase), a closely related GRK (G protein-coupled receptor kinase), was a critical component of PTH-induced receptor down-regulation and homologous cAMP desensitization of PTH-R in osteoblast-like cells (20). GRKs, together with ß-arrestins, are proteins that serve to both uncouple and sequester receptor. In this process, ß-arrestins bound to receptors phosphorylated by GRKs, targeting these receptors toward sequestration pathways (21). Thus, it appears reasonable to anticipate that these processes are likely to play a crucial role in the desensitization of vascular PTH-R.

Desensitization of the PTH-R in the mice overexpressing PTHrP in smooth muscle is precisely what Maeda et al. (8) observed in the current issue of Endocrinology. This is not surprising given the strong susceptibility of PTH-R to be desensitized as discussed above. More intriguing is the partial loss of responsiveness of the vascular tissue not only to PTHrP, but also to acetylcholine and sodium nitroprusside, both in vivo and in vitro. Importantly, the marked decrease of the vasodilatory response to sodium nitroprusside in the transgenic model strongly suggests that PTHrP down-regulates the expression of soluble guanylyl cyclase/cGMP/PKG complex in VSM, by some autocrine, paracrine, or intracrine signaling pathway(s). Basically, this observation suggests that the overexpression of vasodilatory PTHrP may be compensated by the down-regulation of another vasodilatory system, in this case one or more components of the NO/cGMP system. In support of this, chronic NO formation in NO synthase (NOS)III-/- mutant mice induced no changes in basal coronary flow but strongly activated the formation of vasodilatory prostaglandins (22). Even more important in the present context, increasing evidence indicates that the expression of NOSIII, which is expressed in VSM cells as well as in endothelial cells, can be dynamically regulated by a number of physical and (patho)physiological stimuli (23). Down-regulation of NOSIII expression has been documented in rat cardiac myocytes by sustained elevation of cAMP both in vivo and in vitro (24). This latter finding provides an attractive hypothesis to be explored in transgenic mice overexpressing PTHrP because the adenylyl/cAMP/PKA system is the primary signaling pathway that mediates the vasodilation induced by PTHrP. In addition, it has been proposed that in VSM, cGMP decreases the degradation of cAMP by inhibition of phosphodiesterase III expressed in VSM cells, suggesting that cGMP exerts a potentiating effect on cAMP-mediated relaxing actions (25). This may represent another appealing mechanism that could participate in the decrease of PTHrP-induced vasodilation in transgenic mice overexpressing PTHrP. Regardless of the mechanism underlying the presumed modulation by PTHrP of the expression of some components of the NO/cGMP system, this unexpected finding will undoubtedly add a new chapter in the quest of a role for endogenous PTHrP in the regulation of vascular tone. Clearly, this is an important and promising new area in the PTHrP field which probably will develop rapidly.

In contrast to the regulation by cAMP, the participation of endothelium-derived autacoids and the NO/cGMP system as a critical signaling pathway for PTHrP in VSM appears much more controversial. PTHrP vasodilitation has been shown to be either independent or dependent on the presence of an intact endothelium depending on the vascular bed or the species. For instance, the results obtained by Qian et al. (9), emphasizing the endothelium dependence of the PTHrP vasodilatory response in the aorta of wild-type mice was unexpected, given the absence of endothelium dependence that has been observed previously in rat aorta (26). In rabbit renal vessels (18), PTHrP-induced vasodilation was strongly dependent on both cAMP and NO production but not on an intact endothelium. The reasons for these discrepancies are unclear, but most likely reflect some unusual cross-talk between the cAMP and the NO/cGMP pathways.

In addition to the local vascular wall vasoregulatory role of PTHrP discussed by Clemens and his co-workers in the present issue of Endocrinology (8, 9), there is another noteworthy finding that will have to be taken into account in future studies regarding the role of PTHrP in the regulation of blood pressure and regional hemodynamics. In a recent paper, Nagao et al. (27), elegantly demonstrated that intracerebroventricular injection of PTHrP in rats produces an increase in blood pressure, accompanied by a decrease in heart rate. These actions were abolished by pretreatment with an -blocker suggesting that PTHrP present in the brain may be implicated in the central regulation of blood pressure through sympathetic activation.

For almost 80 yr, the vasodilatory role of PTH or PTH-like molecules in vascular tone regulation has been explored. With the purification and the cloning of PTHrP in 1987, a more focused search for a local paracrine, autocrine, or intracrine role for PTHrP in the regulation of vascular tone, development, and remodeling began. In the past 5–6 yr, transgenic technology has allowed an huge breakthrough in the understanding of the functional role(s) of PTHrP especially as a developmental regulatory peptide. The two transgenic models described by Clemens et al. (8, 9) provide now another important and promising tool to further probe the role of PTHrP in the regulation of vascular tone and mitogenesis. A number of questions can be asked using these models. For instance, what are the physiological and cellular mechanisms relating overexpression of PTHrP in VSM to blood pressure and regional hemodynamics? Thus, will renal plasma flow prove to be the primary cardiovascular physiological target of endogenous PTHrP in these mice lines as shown in humans with exogenous PTHrP? Another key question that is just beginning to unfold is how is the central hypertensive effect of PTHrP related to the local vasodilatory effect of PTHrP? Knowing that angiotensin II up-regulates PTHrP in VSM, and that PTHrP stimulates renal renin secretion and the formation of angiotensin II, how do vascular PTHrP interact with the renin-angiotensin system to regulate renal hemodynamics and blood pressure in these transgenic animals? In the same vein, knowing that endothelin up-regulates PTHrP and that PTHrP inhibits the release of endothelin from endothelium through the NO/cGMP pathway, how does VSM PTHrP interact with endothelin in these mice? How does NO originating from either endothelial cells or VSM cells intervene in the vasodilatory effect of PTHrP, and how does the NO/cGMP system relate to the cAMP cascade? How are nuclear targeting of PTHrP and paracrine pathway(s) of PTHrP functionally discriminated in the vessels of these animals? How does this nuclear targeting influence VSM cell cycle and apoptosis? How are the newly discovered vascular PTH2 receptors and PTH-R functionally discriminated in wild vs. transgenic mice overexpressing PTHrP in the VSM? What are their signaling molecules, paracrine as well as intracrine? What is the role of the VSM PTHrP/PTH-R system as compared with the endothelial PTHrP/PTH system? What would be the response of the vascular wall to injury in these animals? Will it be proven that these animals behave differently in diverse experimental vascular diseases such as hypertension, VSM calcification or endotoxemia? Clearly, the understanding of the normal as well as the pathological vascular roles for PTHrP will soon accelerate owing to the transgenic mice overexpressing PTHrP in VSM developed by Clemens and co-workers (8, 9).

Received January 20, 1999.

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