Aging Is Associated With An Impaired Coronary Microvascular Response To Vascular Endothelial Growth Factor In Patients
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Objective: Vascular endothelial growth factor (VEGF) and downstream activation of AKT and eNOS play an important role in angiogenesis. Clinical trials using VEGF have been performed in patients with severe coronary artery disease (CAD). However, the therapeutic effects of VEGF treatment are limited, and the cause is not fully understood. In order to examine the potential of VEGF to induce an angiogenic response in patients undergoing coronary surgery, we determined age dependent differences in the coronary microvascular dilation response to VEGF before and after cardioplegia and cardiopulmonary bypass (CP/CPB), and atrial tissue expression of downstream mediators involved in VEGF signaling. Methods: The atrial tissue of CAD patients undergoing cardiac surgery was harvested before and after CP/CPB. Coronary microvascular responses to VEGF, nitroprusside, and substance P before CP/CPB were measured as percentage dilation following preconstriction (n=16) with U46619. Patient samples were divided into 2 groups; patients less than 65 (Pt<65) and patient more than 70 years old (Pt>70). The coronary microvascular response before and after CP/CPB was also compared within Pt<65 and Pt>70. Expression of VEGF, VEGFR2, and eNOS and the phosphorylation of AKT in atrial tissue were measured by Western blotting (n=6). Results: The microvascular response to VEGF before CP/CPB in Pt.>70 was impaired as compared to Pt. <65 (p = 0.03). Correlation analysis of all patients demonstrated that the coronary microvascular response to VEGF before CP/CPB was negatively correlated with age (R= 0.65, p=0.03). There was no significant difference in the microvessel response to VEGF (p= 0.24 in Pt<65, p= 0.21 in Pt>70), sodium nitroprusside ( p= 0.20 in Pt<65, p= 0.06 in Pt>70), substance P ( p= 0.12 in Pt<65, p= 0.28 in Pt>70) before and after CP/CPB within either group. Expression of eNOS (p= 0.23 in Pt<65, p=0.79 in Pt>70), VEGFR2 (p= 0.70 in Pt<65, p=0.57 in Pt>70), and phosphorylation of AKT (p= 0.4 in Pt<65, p=0.39 in pt>70) was similar in both groups pre/post-CP/CPB. Atrial VEGF protein expression before CP/CPB was similar in both groups. However, VEGF expression after CP/CPB increased in pt. > 70 (p<0.01), but not in Pt <65 (p=0.20).
Conclusions: The microvessel response to VEGF is impaired with age. This effect is independent of increased protein expression of VEGFR2, eNOS, phosphorylation of AKT. This impaired response to VEGF in aged patients may be associated with the limited therapeutic effects by VEGF.
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