help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sutliff, R. L.
Right arrow Articles by Paul, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sutliff, R. L.
Right arrow Articles by Paul, R. J.
Endocrinology Vol. 140, No. 5 2077-2083
Copyright © 1999 by The Endocrine Society

ARTICLES

Vasorelaxant Properties of Parathyroid Hormone-Related Protein in the Mouse: Evidence for Endothelium Involvement Independent of Nitric Oxide Formation1

Roy L. Sutliff, Craig S. Weber, Jin Qian, Marion L. Miller, Thomas L. Clemens and Richard J. Paul

Departments of Molecular and Cellular Physiology (R.L.S., C.S.W., T.L.C., R.J.P.), Internal Medicine (J.Q., T.L.C.), and Environmental Health (M.L.M.), University of Cincinnati, Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Thomas L. Clemens, Ph.D., Division of Endocrinology and Metabolism, P.O. Box 67076, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0547. E-mail: Clementl{at}uc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PTH-related peptide is produced in vascular smooth muscle and is believed to participate in the local control of vascular tone. The recent identification of mid-region PTHrP peptides, as well as the discovery of multiple receptors in blood vessels, raises new questions concerning the mechanisms by which PTHrP relaxes the vasculature. In this study, we examined these mechanisms in two vascular beds of the mouse. PTHrP-(1–34) and PTH-(1–34), but not PTHrP-(38–64) or PTHrP-(38–94), caused concentration-dependent relaxation of precontracted aortas and reduced the spontaneous phasic activity of the portal vein. PTHrP and PTH-induced aortic relaxations were largely endothelium dependent, whereas an intact endothelium was not necessary for maximal portal vein relaxation. The endothelium-dependent component of PTHrP and PTH-induced aortic relaxations were unaffected by pretreatment with either L-NNA or indomethacin but were abolished by pretreatment with tetrabutyl ammonium. These results demonstrate that the N-terminal portions of PTHrP and PTH are required for their vasorelaxant activity in the mouse. In addition, maximal relaxant activity of PTHrP and PTH in murine aorta is dependent on the endothelium, which appears to involve the generation of an endothelium-derived hyperpolarizing factor.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PTH-RELATED PROTEIN (PTHrP) was originally identified as the tumor-derived peptide responsible for the syndrome of humoral hypercalcemia of malignancy (1). PTHrP and PTH share N-terminal sequence homology, which enables both proteins to activate a common G protein-linked receptor that is expressed in bone, kidney, and several other tissues (2). In contrast to PTH, which is produced exclusively by the parathyroid gland, PTHrP is synthesized in many normal fetal and adult tissues (3).

Although PTH has long been known to relax vascular smooth muscle and to acutely lower blood pressure, its relative importance as a normal physiological regulator of cardiovascular hemodynamics has been debated (4). This is in part due to the fact that supraphysiological concentrations of the hormone were often required to produce vasorelaxant effects. The demonstration that both PTHrP and the PTH/PTHrP receptor were expressed in vascular smooth muscle (5, 6), together with the finding that PTHrP had relaxant activity in vascular and other smooth muscle beds (7), suggested that PTHrP may serve in an autocrine/paracrine fashion to control the vasculature. In addition, transgenic mice which selectively overexpress PTHrP in vascular smooth muscle developed hypotension consistent with the predicted role of this protein as a local vasodilator (7A ).

PTHrP is subject to posttranslational processing to produce both N-terminal peptides, mid-region PTHrP fragments (8), and possibly also C-terminal forms (9). Mid-region PTHrP peptides, which lack the PTH-like N-terminal region (10), likely activate receptors distinct from the PTH/PTHrP receptor and would be expected to exhibit a biological profile different from N-terminal PTHrP peptides. Consistent with this notion are studies that showed that N-terminal PTHrP fragments or recombinant PTHrP-(1–141) exhibited biological effects similar to those of PTH, whereas mid-region PTHrP peptides have been shown to uniquely stimulate transplacental calcium transport (11). These data suggest the existence of distinct PTHrP receptors that would be activated by PTHrP forms lacking the PTH-homologous N-terminal portion of the molecule. However, this putative mid-region receptor has yet to be identified. On the other hand, a new receptor, termed the PTH-2 receptor, was recently cloned (12) and shown to be expressed in brain, pancreas and several other tissues including vascular tissues (13). Although the exact structure of the native ligand for the PTH type 2 receptor has yet to be characterized (14), studies to date in cells transfected with recombinant PTH type 2 receptors suggest that it preferentially binds PTH and is relatively unresponsive to N-terminal PTHrP fragments (12, 15).

Relatively little information is available on the mechanisms and signal transduction events that mediate vasorelaxation by PTH-related peptides. In primary rat aortic vascular smooth muscle cells and in A10 vascular-derived smooth muscle cells stably expressing the PTH/PTHrP type 1 receptor, synthetic N-terminal fragments of both PTH and PTHrP increased cellular cAMP production whereas mid-region and C-terminal fragments did not (16, 17). In this study, effective signaling through the phospholipase C pathway was achieved by overexpressing Gq, Gq11 or Gq13 (17). In rat aortic strip preparations, relaxation of precontracted strips by PTHrP-(1–34) was associated with both increased cAMP production and decreased intracellular calcium (18). These results are compatible with activation of the PTH/PTHrP type 1 receptor.

The existence of multiple PTHrP forms and several receptors prompts new questions concerning the mechanisms by which PTHrP alters vascular contractility. In the present study, we investigated the mechanisms by which PTHrP and related peptides induce vasorelaxant activity in two separate blood vessel beds of the mouse.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Vessel preparation
Nine-week-old FVB/N mice (Taconic Farms, Inc., Germantown NY) were killed by CO2 asphyxiation. The animal studies were done in accordance with and approval by the local I.A.C.U.C. Aortas were dissected and prepared for analysis as previously described (19). Briefly, vessels were rinsed in cold bicarbonate buffered physiological saline solution (PSS), and loose fat and connective tissue were removed. PSS contained (mmol/liter): 118 NaCl, 4.73 KCl, 1.2 MgSO4, 0.025 EDTA, 1.2 KH2PO4, 2.5 CaCl2, 11 glucose, and buffered with 25 NaH2CO3,; pH, when bubbled with 95%O2/5% CO2 was 7.4 at 37 C. The endothelium was removed by gently rubbing the ring between thumb and forefinger. The efficiency of endothelium removal using this method was confirmed histologically as described previously (20) and by demonstrating the loss of an endothelium-dependent relaxation to acetylcholine. Endothelium removal did not significantly affect the amount of force generated in response to phenylephrine (PE) administration (data not shown).

Portal veins were prepared as described (21). Briefly, vessels were tied with 4–0 suture at each end (between the hepatic bifurcation of the vein and the anterior mesenteric vein), splayed longitudinally, and then excised. In experiments requiring denuded portal vein, the intima of the open vessel was rubbed with a cotton swab. The efficiency of endothelium removal from the portal vein was confirmed histologically. Vessels were fixed in the bath and then dehydrated through a series of graded ethanols and propylene oxide. After embedding in Spurr’s resin 1.5-mm thick longitudinal sections were cut and stained with toluidine blue for light microscopy. Total lengths of the portal vein at the lumen and lengths, which were covered with endothelium, were digitized using SigmaScan Pro software and a Summagraphics digitizing tablet.

Aorta force measurements
Aortic rings were threaded with two triangular 100-µm stainless steel wires; each completed mounting formed a double triangle. The aorta and holder were then mounted on a hook that was attached to a Harvard Apparatus Differential Capacitor Force Transducer (Holliston, MA). Resting tension on each aorta was set to 30 mN, to approximate an in vivo aortic pressure of approximately 100 mmHg, and this passive tension was maintained throughout the experiment. The effects of different PTH-related peptides on basal aortic tension and on aortas contracted with PE were determined. Data were obtained using MP100W hardware and analyzed using AcqKnowledge Software (Biopac, Goleta, CA).

Portal vein force measurements
Experiments were conducted on isometrically mounted endothelium-intact and denuded portal veins at optimal tension; this was established by adjusting the length of the vessels to a point where maximum peak-to-peak oscillations of spontaneous isometric contractions were observed. Following two sequential stimulations with 15 mM KCl, concentration-isometric force curves were generated in response to PTHrP and related peptides. Force measurements were obtained using the Biopac apparatus as described above. Mechanical analysis included the determination of the tension-time integral over a one minute period.

Measurement of cAMP production
Production of cAMP was determined in near confluent monolayers of UMR-106 cells grown in 24-multiwell plates. Cells were incubated with peptides or vehicle for 5 min in 1 ml medium at 37 C in the presence of 0.2 mM 3-isobutyl-1-methylxanthine. The reaction was terminated by aspirating the medium and adding 0.5 ml of 1 N HCl. The dried extract was kept at -70 C until assay, at which time it was reconstituted with sodium acetate buffer, pH 6.2. Assay of cAMP was carried out by RIA as described (22).

Statistics
Data from concentration-response curves (endothelium dependence and PTH vs. PTHrP) were compared using two-way ANOVA for each. Data from studies using pharmacological antagonists to block PTHrP and PTH-mediated relaxation were compared using one-way ANOVA. Significance was defined as P < 0.05 for all tests.

Chemicals
Synthetic human PTHrP-(hPTHrP)-(1–34), PTHrP-(38–64), human PTH-(hPTH)1–34, rat PTH-(rPTH)-1–34 were purchased from Bachem California, Inc. (Torrance, CA). Synthetic human PTHrP-(38–94) was provided by Dr. Andrew Stewart, Yale University. Peptides were stored at -20 C in 0.01 N acetic acid. Phenylephrine, acetylcholine chloride, n-{omega}-nitro L-arginine, tetrabutylammonium chloride, and indomethacin were from Sigma Chemical Co. (St. Louis, MO).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PTHrP/PTH induced relaxation of mouse aortic rings
To determine the relaxant properties of PTHrP-(1–34), intact and denuded aortic rings were isometrically mounted in the same bath and precontracted with 0.3 µM PE, a concentration that produced 80% maximal contraction. Consecutive addition of either PTHrP-(1–34) or hPTH-(1–34) was associated with desensitization as demonstrated by a marked reduction in the relaxation response to a second administration of peptide (Fig. 1Go). Concentration-response curves to PTHrP-(1–34) using one concentration per aorta were generated as shown in Fig. 2Go. Endothelium-containing aortas showed a greater relaxation response than denuded aortas at all concentrations of PTHrP-(1–34) (P < 0.05). ED50 values were lower by an order of magnitude in aortas with an intact endothelium (1.4 ± 0.4 nM vs. 14.0 ± 3.3 nM; P < 0.05).



View larger version (12K):
[in this window]
[in a new window]
  		Figure 1. Effects of PTH (left panels) and PTHrP (right panels) on endothelium-intact (upper) and denuded (lower) aortas. Vessels were isometrically mounted, precontracted with 0.3 µM phenylephrine (PE), and relaxation was monitored following the addition of 30 nM hPTHrP-(1–34) or hPTH-(1–34). After a washout, vessels were exposed to a second dose of each peptide. Desensitization to a second stimulation was observed for both PTHrP and PTH. The efficiency of endothelium removal was confirmed by demonstrating loss of relaxation to acetylcholine (10 µM).

 


View larger version (6K):
[in this window]
[in a new window]
  		Figure 2. Concentration-relaxation relationships for PTHrP (1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 ) in endothelium containing ({blacksquare}) and denuded aortas ({square}). Vessels were isometrically mounted and contracted with 0.3 µM phenylephrine. PTHrP-(1–34) was administered to generate relaxation relationships. Aortas with an intact endothelium relaxed to a greater extent than denuded aortas (P < 0.05). Each data point represents the % relaxation observed in five separate aortas (mean ± SEM).

 
Effects of PTHrP and PTH on the portal vein
Fig. 3Go shows the effects of PTHrP-(1–34) and hPTH-(1–34) on the phasic activity of the mouse portal vein. Both PTHrP-(1–34) and hPTH-(1–34) markedly reduced the spontaneous activity of the portal vein in a concentration-dependent manner. In contrast to the results in the aorta, desensitization was not observed to either cumulative or consecutive additions of PTHrP-(1–34) or hPTH-(1–34) in the portal vein. In addition, removal of the endothelium as evidenced by the histological sections (Fig. 4AGo) had no effect on the relaxant responses elicited by either PTHrP-(1–34) (Fig. 4BGo) or hPTH-(1–34) (data not shown).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 3. Reduction of phasic contractility of mouse portal veins in response to PTHrP and PTH. Portal veins were isometrically mounted and increasing concentrations of hPTHrP (1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 ) (upper panel) and hPTH-(1–34) (lower panel) were added. No desensitization to PTHrP-(1–34) or hPTH-(1–34) was observed.

 


View larger version (22K):
[in this window]
[in a new window]
  		Figure 4. A, Representative sections of endothelium-intact (left panel) and denuded (right panel) mouse portal veins. Longitudinal sections of portal vein were stained with toluidene blue and the degree of endothelial coverage determined. Figures were generated with a Nikon Spot color camera, converted to gray-scale and sharpened and labeled in Adobe PhotoShop. Arrows indicate endothelial coverage observed adjacent to the lumen (L). Endothelium-intact portal veins showed greater than 70% coverage and endothelium denuded portal veins less than 10% coverage (data not shown) B, Concentration-tension time integral relationships for PTHrP in endothelium-intact and denuded mouse portal veins. Isometrically mounted portal veins with ({blacksquare}) or without endothelium ({square}) were exposed to hPTHrP-(1–34). Tension-time integrals were determined over a 1-min period. Each point represents the mean ± SEM of six portal veins.

 
We next compared the effects of several different fragments of PTH and PTHrP in endothelium-intact mouse aorta and portal vein preparations. None of the peptides had any significant effect in noncontracted aortas (data not shown). N-terminal fragments of PTH and PTHrP elicited potent relaxant activity in PE precontracted aortic rings (Table 1Go) and phasic activity of portal veins (Fig. 5Go) with the rank order of potency being rPTH-(1–34) > PTHrP-(1–34) > hPTH-(1–34). This order of potency was the same as that observed for cAMP stimulatory activity of these same batches of peptides as determined in rat UMR-106 osteoblast-like cells. ED50 values estimated from concentration-response curves for rPTH-(1–34), PTHrP-(1–34) and hPTH-(1–34), were 0.45, 0.66, and 8.5 µM, respectively. Neither PTHrP-(38–64) or PTHrP-(38–94) had any significant contractile (not shown) or relaxant action on either aorta or portal vein (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Relaxant activity of PTH and PTHrP-related peptides on mouse aorta and portal vein

 


View larger version (7K):
[in this window]
[in a new window]
  		Figure 5. Concentration-tension time integral relationships for hPTHrP-(1–34) ({blacksquare}); hPTH-(1–34) (•), and rPTH-(1–34) ({blacktriangleup}) in endothelium-intact portal veins. Isometrically mounted endothelium-intact portal veins were exposed to increasing concentrations of PTHrP-related peptides. ED50 values were 0.4 ± 0.08 nM, 5.2 ± 2.6 nM and 1.2 ± 0.008 nM for rPTH-(1–34), hPTH-(1–34), hPTHrP-(1–34), respectively. Tension-time integrals were determined over a 1-min period. Each point represents the mean ± SEM of six portal veins.

 
Antagonism of endothelium-dependent relaxation by PTHrP and PTH
To investigate the mechanisms mediating the endothelium-dependent component of PTHrP and PTH-induced relaxation of mouse aorta, the effects of antagonists to known endothelium-dependent vasorelaxant pathways were determined. L-NNA, which inhibits nitric oxide synthase, and TBA, a potassium channel blocker that interferes with EDHF, have been used to differentiate between endothelium-dependent relaxations mediated by NO (EDNO) and hyperpolarization (EDHF) (23). Neither L-NNA, a competitive inhibitor of nitric oxide synthase, at a concentration (0.2 mM) that blocks acetylcholine-induced endothelium-dependent relaxation (23), nor indomethacin, a cyclooxygenase inhibitor, altered relaxant activity of PTHrP-(1–34) or PTH-(1–34) in the aorta (Fig. 6Go). By contrast, tetrabutyl ammonium (TBA), a potassium channel blocker, virtually abolished the relaxant effects of PTHrP-(1–34) or PTH-(1–34) (P < 0.05).



View larger version (6K):
[in this window]
[in a new window]
  		Figure 6. Inhibition of PTHrP/PTH-mediated relaxation of mouse aorta. Endothelium-intact aortas were isometrically mounted and pretreated with the nitric oxide synthase competitive inhibitor L-NNA (0.2 mM), the cyclooxygenase inhibitor indomethacin (10 µM), or the potassium channel blocker TBA (2 mM). Aortas were contracted with 0.3 µM phenylephrine and relaxation to maximal concentrations (30 nM) of hPTHrP (1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 ) and hPTH (1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 ) was assessed. Results are expressed as the mean ± SEM (n = 6). *, Statistically significant difference compared with control (P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we characterized the vasorelaxant properties of PTHrP and several related peptides in murine aorta and portal vein. N-terminal fragments of PTHrP and PTH relaxed precontracted aortic rings and decreased spontaneous contractions in portal vein preparations in a concentration-dependent manner. By contrast, neither PTHrP-(38–64) or PTHrP-(38–94) affected contractility of the aorta or portal vein. Therefore, the ability of PTHrP to cause relaxation of mouse vascular smooth muscle appears to require the N-terminal portion of the molecule that contains the PTH homologous region required for binding and activation of the PTH/PTHrP type 1 receptor.

Treatment of mouse aorta with PTHrP-(1–34) was associated with a rapid desensitization of aortic rings to further treatment with PTHrP-(1–34), a phenomenon that has been extensively documented in bone (24), kidney (25), and smooth muscle cells in vitro (26), as well as in rat femoral arteries in vitro (27). Homologous desensitization of G protein-coupled receptors including the PTH/PTHrP receptor appears to be mediated primarily by ligand-dependent phosphorylation and inactivation of the receptor by G protein receptor kinases (GRKs), which are either identical or related to those known to mediate homologous desensitization of the ß adrenergic receptor (28). Interestingly, portal vein preparations did not exhibit desensitization in response to repeated exposure to PTH or PTHrP. The reason for this difference is unclear but may indicate that the PTH type 1 receptor expressed in the portal vein is not subject to phosphorylation and consequent desensitization by a GRK or the portal vein does not contain the GRK responsible for desensitization.

The ability of PTHrP and PTH to induce maximal relaxation was dependent on the presence of an intact endothelium in the aorta but not in the portal vein. This demonstrates that differences exist among the different vessel preparations with respect to the mechanisms by which PTHrP and PTH relax vascular smooth muscle. Interestingly, previous studies in rat vasculature suggested that the endothelium was not required for PTH-induced vasorelaxation (29). Thus, the mechanisms for relaxant effects of PTH and possibly PTHrP may also vary between different species.

The pathways responsible for PTHrP and PTH-induced relaxations of the mouse aorta do not appear to involve generation of prostaglandins or NO, as antagonists to these signaling molecules had no effect on relaxation induced by PTHrP or PTH. The apparent lack of involvement of NO production for PTHrP-induced relaxation is in agreement with previous in vivo studies conducted in spontaneously hypertensive rats (30), which demonstrated that PTH-induced vasorelaxation was not blocked by pretreatment of the animals with the L-arginine analog L-NAME. There is evidence for an endothelium-derived factor distinct from endothelium-derived nitric oxide (EDNO) (31). Endothelium-dependent hyperpolarizing factor, or EDHF, is a putative endothelium-derived diffusible substance that causes transient hyperpolarization of vascular smooth muscle. Recent studies suggest that EDHF is the potassium ion (31A ). Evidence suggesting that EDHF is distinct from EDNO was provided by studies demonstrating that neither methylene blue nor hemoglobin, two agents that inhibit the actions of EDNO, attenuated endothelium-dependent hyperpolarization (32). In addition, nitrovasodilators, which cause relaxation through the production of NO, or application of exogenous NO, cause little or no change in membrane potential (33). Alternatively, it has been suggested that incomplete inhibition of NO production may enable low levels of NO that can activate the TBA-sensitive potassium channel (34). In contrast to the present study suggesting NO-independent endothelial vasoactivity of PTHrP, studies by Massfelder et al. (35) in the isolated perfused rabbit kidney showed that pretreatment of preparations with L-NAME reduced PTHrP-induced vasorelaxation. It is therefore likely that PTHrP induces relaxation by stimulation (or inhibition) of signaling pathways that differ among different vascular beds and possibly also between different species.

In conclusion, we have demonstrated that N-terminal fragments of PTHrP and PTH exert potent vasorelaxant effects on the murine aorta and portal vein. These effects are largely endothelium-dependent in the aorta but independent of endothelium in the portal vein. Vasorelaxant actions of PTH and PTHrP in the aorta do not appear to occur through NO-dependent or eicosanoid pathways. The precise mechanisms by which PTH and PTHrP exert their vasorelaxant effects, the exact nature of the signaling mechanisms, and possible interactions between vascular smooth muscle and endothelial cells remain to be established.


   Acknowledgments
 
We gratefully acknowledge the technical assistance of Anastasia Andringa.


   Footnotes
 
1 This work was supported by Grants HL-09781 (to R.L.S.), HL-54829 (to R.J.P.), and HL-47811 (to T.L.C.) and T-32-HL-07571. Back

Received May 11, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Moseley JM, Martin TJ 1996 Parathyroid hormone-related protein: physiological actions. In Bilezikian JP, Raisz LJ, Rodan GA (eds) Principals of Bone Biology. Academic Press, New York, pp 363–376
  2. Jüppner H, Abou-Samra AB, Uneno S, Gu WX, Potts Jr JT, Segre GV 1988 The parathyroid hormone-like peptide associated with humoral hypercalcemia of malignancy and parathyroid hormone bind to the same receptor on the plasma membrane of ROS 17/2.8 cells. J Biol Chem 263:8557–8560[Abstract/Free Full Text]
  3. Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, Vasavada RC, Weir EC, Broadus AE, Stewart AF 1996 Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76:127–173[Abstract/Free Full Text]
  4. Bukoski RD, Ishibashi K, Bian K 1995 Vascular actions of the calcium-regulating hormones. Semin Nephrol 15:536–549[Medline]
  5. Hongo T, Kupfer J, Enomoto H, Sharifi B, Giannella-Neto D, Forrester JS, Singer FR, Hendy GN, Goltzman D, Fagin JA, Clemens TL 1991 Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation. J Clin Invest 88:1841–1847
  6. Nickols GA, Nickols MA, Helwig JJ 1990 Binding of parathyroid hormone and parathyroid hormone-related protein to vascular smooth muscle of rabbit renal microvessels. Endocrinology 126:721–727[Abstract/Free Full Text]
  7. Mok LL, Nickols GA, Thompson JC, Cooper CW 1989 Parathyroid hormone as a smooth muscle relaxant. Endocr Rev 10:420–436[Abstract/Free Full Text]
  8. Maeda S, Sutliff RL, Qian J, Lorenz JN, Wang J, Tang H, Nakayama T, Weber C, Witte D, Strauch A, Paul RJ, Fagin JA, Clemens TL1999 Targeted overexpression of parathyroid hormone-related protein (PTHrP) to vascular smooth muscle in transgenic mice lowers blood pressure and alters vascular contractility. Endocrinology 140:1815–1825
  9. dePapp AE, Stewart AF 1993 Parathyroid hormone related protein. A peptide of diverse physiologic functions. Trends Endocrinol Metab 4:181–187
  10. Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF 1994 Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev 15:40–60[Abstract/Free Full Text]
  11. Wu TL, Vasavada RC, Yang K, Massfelder T, Ganz M, Abbas SK, Care AD, Stewart AF 1996 Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem 271:24371–24381[Abstract/Free Full Text]
  12. Kovacs CS, Kronenberg HM 1997 Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev 18:832–872[Abstract/Free Full Text]
  13. Usdin TB, Gruber C, Bonner TI 1995 Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2 receptor. J Biol Chem 270:15455–15458[Abstract/Free Full Text]
  14. Usdin TB, Bonner TI, Harta G, Mezey E 1996 Distribution of parathyroid hormone-2 receptor messenger ribonucleic acid in rat. Endocrinology 137:4285–4297[Abstract]
  15. Usdin TB 1997 Evidence for a parathyroid hormone-2 receptor selective ligand in the hypothalamus. Endocrinology 138:831–834[Abstract/Free Full Text]
  16. Behar V, Pines M, Nakamoto C, Greenberg Z, Bisello A, Stueckle SM, Bessalle R, Usdin TB, Chorev M, Rosenblatt M, Suva LJ 1996 The human PTH2 receptor: binding and signal transduction properties of the stably expressed recombinant receptor. Endocrinology 137:2748–2757[Abstract]
  17. Wu S, Pirola CJ, Green J, Yamaguchi DT, Okano K, Jüppner H, Forrester JS, Fagin JA, Clemens TL 1993 Effects of N-terminal, midregion, and C-terminal parathyroid hormone-related peptides on adenosine 3',5'-monophosphate and cytoplasmic free calcium in rat aortic smooth muscle cells and UMR-106 osteoblast-like cells. Endocrinology 133:2437–2444[Abstract/Free Full Text]
  18. Maeda S, Wu S, Jüppner H, Green J, Aragay AM, Fagin JA, Clemens TL 1996 Cell-specific signal transduction of parathyroid hormone (PTH)-related protein through stably expressed recombinant PTH/PTHrP receptors in vascular smooth muscle cells. Endocrinology 137:3154–3162[Abstract]
  19. Ishikawa M, Ouchi Y, Han SZ, Akishita M, Kozaki K, Toba K, Namiki A, Yamaguchi T, Orimo H 1994 Parathyroid hormone-related protein reduces cytosolic free Ca2+ level and tension in rat aortic smooth muscle. Eur J Pharmacol 269:311–317[CrossRef][Medline]
  20. Lalli J, Harrer JM, Luo W, Kranias EG, Paul RJ 1997 Targeted ablation of the phospholamban gene is associated with a marked decrease in sensitivity in aortic smooth muscle. Circ Res 80:506–513[Abstract/Free Full Text]
  21. Liu LH, Paul RJ, Sutliff RL, Miller ML, Lorenz JN, Pun RY, Duffy JJ, Doetschman T, Kimura Y, MacLennan D, Hoying JB, Shull GE 1997 Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3. J Biol Chem 272:30538–30545[Abstract/Free Full Text]
  22. Zhou M, Sutliff RL, Paul R, Lorenz JN, Hoying JB, Haudenschild C, Yin M, Coffin JD, Kong L, Kranias EG, Luo W, Boivin GP, Duffy JJ, Pawlowski SA, Doetschman T 1998 Fibroblast growth factor 2 control of vascular tone. Nat Med 4:201–207[CrossRef][Medline]
  23. Green J, Foellmer O, Kleeman CR, Basic MM 1993 Acute phosphate depletion inhibits the Na+/H+ antiporter in a cultured renal cell line. Am J Physiol 265:F440–F448
  24. Nagao T, Vanhoutte PM 1992 Characterization of endothelium-dependent relaxations resistant to nitro-L-arginine in the porcine coronary artery. Br J Pharmacol 107:1102–1107[Medline]
  25. Pun KK, Ho PW, Nissenson RA, Arnaud CD 1990 Desensitization of parathyroid hormone receptors on cultured bone cells. J Bone Miner Res 5:1193–1200[Medline]
  26. Abou-Samra AB, Goldsmith PK, Xie LY, Juppner H, Spiegel AM, Segre GV 1994 Down-regulation of parathyroid (PTH)/PTH-related peptide receptor immunoreactivity and PTH binding in opossum kidney cells by PTH and dexamethasone. Endocrinology 135:2588–2594[Abstract]
  27. Okano K, Wu S, Huang X, Pirola CJ, Jüppner H, Abou-Samra AB, Segre GV, Iwasaki K, Fagin JA, Clemens TL 1994 Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor and its messenger ribonucleic acid in rat aortic vascular smooth muscle cells and UMR osteoblast-like cells: cell-specific regulation by angiotensin-II and PTHrP. Endocrinology 135:1093–1099[Abstract]
  28. Nyby MD, Hino T, Berger ME, Ormsby BL, Golub MS, Brickman AS 1995 Desensitization of vascular tissue to parathyroid hormone and parathyroid hormone-related protein. Endocrinology 136:2497–2504[Abstract]
  29. Blind E, Bambino T, Huang Z, Bliziotes M, Nissenson RA 1996 Phosphorylation of the cytoplasmic tail of the PTH/PTHrP receptor. J Bone Miner Res 11:578–586[Medline]
  30. Nickols GA, Metz MA, Cline WH 1986 Endothelium-independent linkage of parathyroid hormone receptors of rat vascular tissue with increased adenosine 3',5'-monophosphate and relaxation of vascular smooth muscle. Endocrinology 119:349–356[Abstract/Free Full Text]
  31. Schleiffer R, Pernot F, Gairard A 1995 Endogenous nitric oxide is not involved in acute parathyroid hormone-induced hypotension in rat: effect of hypertension and hypoparathyroid status. Horm Metab Res 27:415–418[Medline]
  32. Komori K, Vanhoutte PM 1990 Endothelium-derived hyperpolarizing factor. Blood Vessels 27:238–245[Medline]
  33. Edwards G, Dora KA, Gardner MJ, Garland CJ, Weston AH1998 K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396:269–272
  34. Chen G, Suzuki H, Weston AH 1988 Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br J Pharmacol 95:1165–1174[Medline]
  35. Beny JL, Brunet PC 1988 Neither nitric oxide nor nitroglycerin accounts for all the characteristics of endothelium-mediated vasodilatation of pig coronary arteries. Blood Vessels 25:308–311[Medline]
  36. Cohen RA, Plane F, Najibi S, Huk I, Malinski T, Garland CJ 1997 Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpolarization of the rabbit carotid artery. Proc Natl Acad Sci USA 94:4193–4198[Abstract/Free Full Text]
  37. Massfelder T, Stewart AF, Endlich K, Soifer N, Judes C, Helwig JJ 1996 Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system. Kidney Int 50:1591–1603[Medline]



This article has been cited by other articles:


Home page
 EndocrinologyHome page
R. Schreckenberg, S. Wenzel, R. M. da Costa Rebelo, A. Rothig, R. Meyer, and K.-D. Schluter
Cell-Specific Effects of Nitric Oxide Deficiency on Parathyroid Hormone-Related Peptide (PTHrP) Responsiveness and PTH1 Receptor Expression in Cardiovascular Cells
Endocrinology, August 1, 2009; 150(8): 3735 - 3741.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. J. Mahon, T. M. Bonacci, P. Divieti, and A. V. Smrcka
A Docking Site for G Protein {beta}{gamma} Subunits on the Parathyroid Hormone 1 Receptor Supports Signaling through Multiple Pathways
Mol. Endocrinol., January 1, 2006; 20(1): 136 - 146.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
Y. Gao and J. U. Raj
Parathyroid hormone-related protein-mediated responses in pulmonary arteries and veins of newborn lambs
Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L60 - L66.
[Abstract] [Full Text] [PDF]

Home page
 Reproductive SciencesHome page
F. Meziani, B. Van Overloop, F. Schneider, and A. Gairard
Parathyroid Hormone-Related Protein-induced Relaxation of Rat Uterine Arteries: Influence of the Endothelium During Gestation
Reproductive Sciences, January 1, 2005; 12(1): 14 - 19.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
G. W. Okunade, M. L. Miller, G. J. Pyne, R. L. Sutliff, K. T. O'Connor, J. C. Neumann, A. Andringa, D. A. Miller, V. Prasad, T. Doetschman, et al.
Targeted Ablation of Plasma Membrane Ca2+-ATPase (PMCA) 1 and 4 Indicates a Major Housekeeping Function for PMCA1 and a Critical Role in Hyperactivated Sperm Motility and Male Fertility for PMCA4
J. Biol. Chem., August 6, 2004; 279(32): 33742 - 33750.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. J. Mahon, J. A. Cole, E. D. Lederer, and G. V. Segre
Na+/H+ Exchanger-Regulatory Factor 1 Mediates Inhibition of Phosphate Transport by Parathyroid Hormone and Second Messengers by Acting at Multiple Sites in Opossum Kidney Cells
Mol. Endocrinol., November 1, 2003; 17(11): 2355 - 2364.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. L. Sutliff, S. Dikalov, D. Weiss, J. Parker, S. Raidel, A. K. Racine, R. Russ, C. P. Haase, W. R. Taylor, and W. Lewis
Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide
Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2363 - H2370.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. N Carr, R. L Sutliff, C. S Weber, P. B Allen, P. Greengard, P. de Lanerolle, E. G Kranias, and R. J Paul
Is myosin phosphatase regulated in vivo by inhibitor-1? Evidence from inhibitor-1 knockout mice
J. Physiol., July 15, 2001; 534(2): 357 - 366.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. Mizuno, N. Ono, and T. Ohhashi
Parathyroid hormone-related protein-(1-34) inhibits intrinsic pump activity of isolated murine lymph vessels
Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H60 - H66.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. Zhao, R. L. Sutliff, C. S. Weber, J. Wang, J. Lorenz, R. J. Paul, and J. A. Fagin
Smooth Muscle-Targeted Overexpression of Insulin-Like Growth Factor I Results in Enhanced Vascular Contractility
Endocrinology, February 1, 2001; 142(2): 623 - 632.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sutliff, R. L.
Right arrow Articles by Paul, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sutliff, R. L.
Right arrow Articles by Paul, R. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals