Stem cell factor and c-kit are expressed by and may affect vascular SMCs through an autocrine pathway

J Surg Res. 2004 Aug;120(2):288-94. doi: 10.1016/j.jss.2004.01.005.

Abstract

Introduction: Stem cell factor (SCF) is a membrane-bound and soluble growth factor that activates the c-kit tyrosine kinase receptor. Given the similarities between c-kit and platelet-derived growth factor (PDGF) receptors, we hypothesized that similar to PDGF, SCF/c-kit signaling may play a role in smooth muscle cell (SMC) function and thus the development of intimal hyperplasia.

Materials and methods: Human saphenous vein SMCs were harvested from veins procured at the time of bypass grafting. Carotid arteries from rats that were balloon injured (n = 12) at variable time points were compared to sham-operated controls (n = 3). Expression of SCF and c-kit was measured by immunohistochemistry (IHC) and Western blotting.

Results: Western blotting revealed that human SMCs express membrane-bound SCF. In separate experiments, we found that this growth factor undergoes proteolytic cleavage to its soluble form following exposure to matrix metalloproteinase-9 (MMP-9), a ubiquitous MMP released at the time of arterial injury. We next evaluated in human SMCs, expression of the SCF receptor, c-kit. Western blotting of human SMC lysates revealed minor but consistent expression of c-kit. IHC demonstrated c-kit expression to be localized to the media. To determine if c-kit is up-regulated during the development of intimal hyperplasia, we evaluated expression of this receptor in a rat carotid balloon injury model. Quantification of IHC staining on injured vessels revealed that c-kit expression within the media was significantly increased at 3, 7, 14, and 28 days following injury (28.1, 30.8, 16, and 10.4% increase over sham controls, respectively, P < 0.05). Furthermore, c-kit expression was prominent within the neointima and maximal at 7 days (53.4 +/- 7.8% of area c-kit positive).

Conclusion: Human vascular SMCs express the growth factor SCF and its receptor, c-kit. SCF is released from its membrane-bound form via MMP-9. This finding and the dramatic increase in c-kit expression observed in the rat carotid artery after balloon injury suggests SCF/c-kit signaling may affect SMC function via an autocrine pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autocrine Communication*
  • Carotid Artery Injuries / metabolism*
  • Carotid Artery Injuries / pathology
  • Cells, Cultured
  • Humans
  • Hyperplasia
  • Male
  • Matrix Metalloproteinase 9 / pharmacology
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Saphenous Vein
  • Stem Cell Factor / metabolism*
  • Tunica Intima / metabolism
  • Tunica Intima / pathology

Substances

  • Stem Cell Factor
  • Proto-Oncogene Proteins c-kit
  • Matrix Metalloproteinase 9