Date of Award
Doctor of Philosophy (PhD)
Dr. R.M.K.W. Lee
One of the possible contributing factors in the development of hypertension may be an accelerated or premature vascular ageing process, because of some similar structural and functional alterations in the vasculature, including an impaired β-adrenoceptor mediated vascular relaxation and an increase in polyploid smooth muscle cells. The primary objective of this study was to investigate the possible relationship between development of polyploidy and the plasma membrane β-adrenoceptor in cultured smooth muscle cells from the thoracic aortae of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) from 3-4-(prehypertensive), 10-12-(developing hypertensive), and 28-30-weeks (establish hypertensive) of age.
The major findings from this study are: (i) similar to the in vivo state, cultured smooth muscle cells from different age-groups of WKY and SHR contain a heterogeneous population of mononucleated and multinucleated cells, as well as diploid and polyploid smooth muscle cells; (ii) the expression of both smooth muscle cell polyploidy and β-adrenoceptor density increases with age in both SHR and WKY, however, this increase was significantly accelerated in SHR as compared to WKY, suggesting an accelerated or premature ageing process may be involved in SHR as compared to WKY; (iii) both SHR and WKY express functional smooth muscle cell β-adrenoceptors but many of the β-adrenoceptors expressed on cultured SHR smooth muscle cells are not coupled to adenylate cyclase; (iv) elevation of intracellular cAMP levels either by agonist activation of β-adrenoceptors or by direct activation of adenylate cyclase in cultured smooth muscle cells from 3-4-week old WKY and SHR and 10-12-week old WKY resulted in an increase in polyploid cells; (v) a β-adrenoceptor antagonist only partially inhibited the isoproterenol-stimulated increase in polyploid smooth muscle cells in both SHR and WKY; and, (vi) the development of polyploid SMC via the β-adrenoceptor-Gs-protein-adenylate cyclase-cAMP pathway is more efficient in cells from WKY compared to SHR.
From these findings, I conclude that: (i) the vascular β-adrenoceptor mediated signalling pathway plays a role in the development of polyploid smooth muscle cells; and, (ii) additional intracellular pathways, independent of the β-adrenoceptor-cAMP intracellular mediated signalling pathway, are involved in the development of smooth muscle cell polyploidy.
Since it is the resistance arteries (which show no significant increase of polyploid smooth muscle cells with age and/or duration of hypertension) and not the elastic large arteries (aorta) which play a significant role in the development of hypertension, these findings have more relevance to the premature ageing process than to the development of hypertension.
Conyers, Roop B., "β-adrenoceptors, adenosine 3',5'-cyclic monophosphate and polyploidy in vascular smooth muscle cells from different age-groups of spontaneously hypertensive and normotensive Wistar-Kyoto rats" (1996). Open Access Dissertations and Theses. Paper 2257.