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Parathyroid hormone–related peptide is a naturally occurring, protein kinase A–dependent angiogenesis inhibitor

Abstract

Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone–related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone–related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone–related peptide. These studies show that parathyroid hormone–related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.

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Figure 1: PTHrP inhibits angiogenesis in vivo.
Figure 2: Inhibition of angiogenesis and tumor growth by PTHrP gene delivery.
Figure 3: The N-terminal 34 amino acids of PTHrP inhibit endothelial cell migration in vitro and angiogenesis in vivo.
Figure 4: PTHrP amino acids 1–10 are sufficient to inhibit endothelial cell migration in vitro and angiogenesis in vivo.
Figure 5: PTHrP inhibits migration by blocking Rac activation in a PKA-dependent manner.
Figure 6: PTHrP mediated inhibition of angiogenesis is protein kinase A–dependent.

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Acknowledgements

This work was supported by grants from the National Institutes of Health to J.A.V. (CA71619 and CA83133), to R.T. (AR47347) and to L.J.D. (DK60588). R.T. and L.J.D. are supported by the Department of Veterans Affairs. J.A.V. and L.J.D. are members of the University of California, San Diego Cancer Center.

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Correspondence to Judith A. Varner.

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Bakre, M., Zhu, Y., Yin, H. et al. Parathyroid hormone–related peptide is a naturally occurring, protein kinase A–dependent angiogenesis inhibitor. Nat Med 8, 995–1003 (2002). https://doi.org/10.1038/nm753

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