Effects of hypoxia on proliferation and signal transduction pathways in pulmonary and systemic vascular fibroblast cells

Welsh, David John (2001) Effects of hypoxia on proliferation and signal transduction pathways in pulmonary and systemic vascular fibroblast cells. PhD thesis, University of Glasgow.

Abstract

When pulmonary hypertension occurs in the face of hypoxia there is remodelling of all 3 layers of the pulmonary vessels, but in particular, there is an increase in number of adventitial fibroblasts. Hypoxia causes vasoconstriction in the pulmonary circulation and vasodilation in the systemic. We hypothesised that the remodelling process might be circulation specific and that there are fundamental differences in oxygen sensing and cell signalling between systemic and pulmonary artery cells in response to hypoxia. Both the mitogen-activated protein kinases (MAP kinase) and the stress-activated protein kinases (SAPK) have been shown to play an important role in cellular growth and proliferation in a number of cell systems. The aim of this present study was to examine the effects of acute and chronic hypoxia on proliferation and determine a role for MAP/SAP kinases in response to both G-protein linked receptor agonists and growth factors in fibroblasts from the pulmonary and systemic arteries of cows and rats. In bovine pulmonary artery fibroblast (BPAF) cells short-term exposure (24h) to 2% oxygen (hypoxia) increased proliferation. In the presence of certain agonists hypoxia augmented this proliferation. This enhanced proliferation was not seen in fibroblasts from the mesenteric artery (BMAF). Hypoxia also gave rise to increases in the second messenger, inositol 1,4,5-trisphosphate (IP3) mass in conjunction with the agonists responsible for increased proliferation in the BPAF cells. There was no increase in IP3 mass in the BMAF cells. The effect of acute hypoxia on activity of MAP kinase isoforms was also studied. Hypoxia was found to increase the SAP kinase isoforms, p38 MAP kinase and c-jun N-terminal kinase (JNK) without effecting MAP kinase in BPAF cells. In contrast, hypoxia had no effect on the MAP kinase family of enzymes in BMAF cells. Puhnonaiy artery fibroblasts from chronically hypoxic rats (HRPAF) displayed increased proliferation to serum and constitutive increases in p38 and MAP kinase, with no increase in JNK when compared to control cells even when maintained in normoxic conditions. This increase in proliferation was not observed in aortic fibroblasts from chronically hypoxic rats (HRAF). 5-HT, with the addition of low serum levels, increased proliferation in the rat cells and could further enhance the phosphorylation of p38 and MAP kinase in HRPAF cells. Specific 5-HT agonists and antagonists showed the 5-HT2A receptor to be the relevant receptor responsible for these observations. The results reported in this thesis show for the first time that hypoxia can increase fibroblast proliferation in cells from pulmonary arteries whilst having so such effect in those from the systemic arteries. In addition, specific signalling pathways have been highlighted which are activated in the pulmonary cells to hypoxia but not in those of the systemic arteries.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Andrew Peacock
• Keywords: Cellular biology.
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Supervisor, not known
• Date of Award: 2001
• Depositing User: Enlighten Team
• Unique ID: glathesis:2001-72147
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 May 2019 12:48
• Last Modified: 20 Jun 2022 11:16
• Thesis DOI: 10.5525/gla.thesis.72147
• URI: https://theses.gla.ac.uk/id/eprint/72147