Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo

Laurie K. Bale, Zachary T. Resch, Sara L. Harstad, Michael T. Overgaard, Cheryl A Conover

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) functions to increase local IGF-I bioactivity. In this study, we used transgenic mice that constitutively express human PAPP-A in arterial smooth muscle to test the hypothesis that overexpression of PAPP-A enhances vascular smooth muscle cell (SMC) response to IGF-I in vivo. PAPP-A transgenic (Tg) and wild-type (WT) mice underwent unilateral carotid ligation, a model of injuryinduced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation 5 days after carotid ligation. However, PAPP-A Tg mice had 70-75% less neointima than WT at 5 and 10 days postligation, with a significant reduction in occlusion of the ligated artery. WT and PAPP-A Tg mice had equivalent increases in medial area and vessel remodeling postligation. There was little change in medial area and no evidence of neointima in the contralateral carotid of WT or PAPP-A Tg mice. Both WT and PAPP-A Tg carotids exhibited signs of dedifferentiation of SMC, which precedes the increase in proliferation and migration that results in neointimal formation. However, the number of proliferating cells in the media and neointima of the ligated PAPP-A Tg artery was reduced by 90% on day 5 postsurgery compared with WT. This decrease was associated with a significant decrease in an in vivo marker of IGF-I bioactivity and reduced IGF-I-stimulated receptor phosphorylation ex vivo. These data suggest differential effects of chronic (transgenic) and transient (endogenous) PAPP-A expression on neointimal formation following vascular injury that may be due in part to the differential impact on IGF-I signaling.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume304
Issue number2
DOIs
StatePublished - Jan 15 2013

Fingerprint

Pregnancy-Associated Plasma Protein-A
Vascular Smooth Muscle
Wounds and Injuries
Transgenic Mice
Insulin-Like Growth Factor I
Neointima
Smooth Muscle Myocytes
Ligation
Arteries
IGF Type 1 Receptor
Vascular System Injuries
Hyperplasia
Smooth Muscle

Keywords

  • Carotid ligatio
  • Hyperplasia
  • Insulin-like growth factor I
  • Pregnancy-associated plasma protein-A
  • Restenosis
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo. / Bale, Laurie K.; Resch, Zachary T.; Harstad, Sara L.; Overgaard, Michael T.; Conover, Cheryl A.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 304, No. 2, 15.01.2013.

Research output: Contribution to journalArticle

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abstract = "Pregnancy-associated plasma protein-A (PAPP-A) functions to increase local IGF-I bioactivity. In this study, we used transgenic mice that constitutively express human PAPP-A in arterial smooth muscle to test the hypothesis that overexpression of PAPP-A enhances vascular smooth muscle cell (SMC) response to IGF-I in vivo. PAPP-A transgenic (Tg) and wild-type (WT) mice underwent unilateral carotid ligation, a model of injuryinduced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation 5 days after carotid ligation. However, PAPP-A Tg mice had 70-75{\%} less neointima than WT at 5 and 10 days postligation, with a significant reduction in occlusion of the ligated artery. WT and PAPP-A Tg mice had equivalent increases in medial area and vessel remodeling postligation. There was little change in medial area and no evidence of neointima in the contralateral carotid of WT or PAPP-A Tg mice. Both WT and PAPP-A Tg carotids exhibited signs of dedifferentiation of SMC, which precedes the increase in proliferation and migration that results in neointimal formation. However, the number of proliferating cells in the media and neointima of the ligated PAPP-A Tg artery was reduced by 90{\%} on day 5 postsurgery compared with WT. This decrease was associated with a significant decrease in an in vivo marker of IGF-I bioactivity and reduced IGF-I-stimulated receptor phosphorylation ex vivo. These data suggest differential effects of chronic (transgenic) and transient (endogenous) PAPP-A expression on neointimal formation following vascular injury that may be due in part to the differential impact on IGF-I signaling.",
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AU - Resch, Zachary T.

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