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 Toft Overgaard, Cheryl A. Conover

Research output: Contribution to journalJournal articleResearchpeer-review

12 Citations (Scopus)

Abstract

Pregnancy associated plasma protein-A (PAPP-A) functions to increase local insulin-like growth factor (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 injury-induced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation five days after carotid ligation. However, PAPP-A Tg mice had 70-75% less neointima than WT at five and ten days post-ligation 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 post-ligation. 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 de-differentiation 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% at day 5 post-surgery compared to 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 differential impact on IGF-I signaling.
Original languageEnglish
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Volume304
Issue number2
Pages (from-to)E139-E144
ISSN0193-1849
DOIs
Publication statusPublished - Jan 2013

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