Arterial smooth muscle cells (SMCs) from the systemic and pulmonary circulations experience a broad range of oxygen concentrations under physiological conditions. The hypoxic response, however, has been inconsistent, with both enhanced proliferation and growth arrest being reported. This variability precludes a definitive conclusion regarding the role of oxygen tension in arterial disease. In the first part of this study, we determined if hypoxia elicits different proliferative and apoptotic responses in human aortic SMCs (HASMCs) incubated under conditions which do or do not result in cellular ATP depletion and whether these effects are relevant to vascular remodeling in vivo. Gene expression profiling was used to identify potential regulatory pathways. In HASMCs incubated at 3% O2, proliferation and progression through G1/S interphase are enhanced. Incubation at 1% O2 reduced proliferation, delayed G1/S transition, increased apoptosis and cellular ATP levels were reduced. In aorta and mesenteric artery from hypoxia exposed rats, both proliferation and apoptosis are increased after 48hrs. p53 and p21expression is differentially affected in HASMCs incubated at 1% and 3% O2. Hypoxia induces a state of enhanced cell turnover, conferring the ability to remodel the vasculature in response to changing tissue metabolic needs while avoiding the accumulation of mutations that may lead to malignant transformation or abnormal vascular structure formation. A unifying hypothesis in which events at the G1/S transition and apoptosis activation are coordinated by effects on p53, p21, their downstream effector genes and regulatory factors is proposed. Differences in the contractile responses of systemic and pulmonary arterial smooth muscle cells to hypoxia are well studied. Differences in proliferation and survival are anticipated because of differences in embryonal cell origin, oxygen concentrations within their respective microenvironments and in cellular energetics but these responses have not been directly compared. In the second part of the study, human pulmonary arterial SMCs (HPASMCs) proliferated at oxygen concentrations which inhibited cell growth in HASMCs. HPASMCs survived and maintained their intracellular ATP levels at levels of hypoxia sufficient to deplete ATP and induce apoptosis in HASMCs. In vivo studies in rats show proliferation and apoptosis in main or branch PASMCs only after 7 days of hypoxia. VSMCs are able to proliferate under hypoxic conditions as long as cellular ATP levels are maintained. HPASMCs have an enhanced capacity to maintain cellular energy status compared to HASMCs and hence their viability is preserved and the proliferative response predominates at lower oxygen concentrations.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/19257 |
| Date | 03 March 2010 |
| Creators | Basu Ray, Julie |
| Contributors | Ward, Miachel E. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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