الملخص الإنجليزي
Background: Most of CVD research is focused on developing pharmacological interventions to mitigate the effects of its major risk factors such as hypertension and dyslipidemia, while little is known about aging-associated physiological changes, particularly those occur in the coronary circulation, Myogenic behavior of blood vessels is one of the important mechanisms for regulation of blood flow in response to changes in intraluminal pressure, where vessels respond to pressure elevation by constriction and pressure reduction by relaxation. Aims and objectives: This work aimed at studying the relation between aging and coronary vascular dysfunction, specifically, aging-associated changes of the coronary myogenic tone being an important factor in regulating coronary vascular resistance and, in turn, blood flow to the myocardium. The main objective of the study was to ascertain if aging impairs myogenic tone of resistance coronary arteries and whether calcium influx through L-type voltage-gated calcium channels (LTCC) contributes to this effect. Methods: Young (3-4 months) and old (22-26 months) F344 rats were used to detect aging-associated changes of coronary myogenic tone. Whole vessel intracellular calcium concentration and LTCC currents and expression of its pore forming alC-subunit were measured. These parameters were studied in small coronary arteries (~100 um) that are known to contribute to resistance to blood flow as well as in large arteries (300-500 um). The study was conducted at three experimental levels. First; functional, using ratiometric (Fura-2AM) Ca2+ imaging and video edge detection of outer diameters of coronary arteries perfused under variable intraluminal pressures (20-100 mmHg) to detect changes in intracellular Ca2+ signaling and vessel diameters. Second, electrophysiological, using whole-cell patch-clamp technique to measure membrane LTCC currents in isolated coronary vascular smooth muscle cells, and, third, molecular, using quantitative PCR to measure expression level of mRNA of a1C subunit. Results: Aging abolished myogenic response and significantly reduced myogenic tone of small coronary arteries at all intraluminal pressures tested. This reduction in tone was associated with reduced intracellular Ca2+ levels. Peak LTCC current densities were reduced by 58 % and expression of mRNA of pore forming subunit (alc) of LTCC was reduced by - 50%. In the large arteries of old rats, the myogenic tone was abolished and intracellular Ca2+ was significantly reduced by ~72%. However, both LTCC current densities and expression of mRNA encoding alC were unaltered with aging. Conclusion: Taken together, the findings of this study demonstrated that LTCC were responsible for the increase in intracellular Ca2+ required to establish myogenic tone of small coronary arteries from young and partly from old rats. Aging significantly reduced myogenic tone of small coronary arteries by down regulating the expression of mRNA encoding the pore forming subunit of LTCC. The abolished myogenic tone in large arteries cannot be attributed to changes in LTCC expression since the current densities and mRNA encoding a1C was unaltered. Additional age-associated mechanisms such as those involved in regulation of LTCC may be implicated in large arteries. These results also demonstrated that aging differentially affected small and large coronary arteries and therefore results obtained from large arteries should not simply be extrapolated to resistance arteries. The age-related reduction in myogenic tone of coronary arteries may limit the vasodilatory reserve and therefore impair the metabolic regulation of blood flow and hence expose the aged myocardium to ischemia.
