TNF-α induces proliferation or apoptosis in human saphenous vein smooth muscle cells depending on phenotype

Abstract

. TNF-␣ induces proliferation or apoptosis in human saphenous vein smooth muscle cells depending on phenotype. Am J Physiol Heart Circ Physiol 288: H293-H301, 2005. First published September 9, 2004; doi:10.1152/ajpheart.00165.2004.-Tumor necrosis factor (TNF)-␣ is implicated in development of restenotic and atherosclerotic vascular lesions, which are pathological processes involving both proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Human VSMCs were recently found to contain heterogeneous subpopulations. We therefore examined whether TNF has different effects on distinct subpopulations of VSMCs. With the use of cloning techniques, two stable subpopulations of VSMCs were isolated from human saphenous vein: spindleand epithelioid-shaped smooth muscle cells (Sp-and Ep-SMCs, respectively). We found that TNF stimulated growth in Sp-SMCs but had a toxic effect on Ep-SMCs. TNF did not induce apoptosis in Sp-SMCs as determined by nuclear staining and cellular DNA electrophoresis. In contrast, the reduction of viability in Ep-SMCs was associated with induction of apoptosis as characterized by cellular DNA fragmentation and nuclear condensation. Higher levels of the TNF-R1 receptor subtype were detected in membrane preparations from Ep-SMCs than in membranes from Sp-SMCs. Activation of caspase-3 was also selectively induced in Ep-SMCs but not in SpSMCs. Cycloheximide, an inhibitor of protein synthesis, enhanced the toxicity of TNF in Ep-SMCs. This effect of cycloheximide was not seen in Sp-SMCs. The data presented here demonstrate for the first time that TNF either promotes growth or induces apoptosis in human VSMCs depending on phenotype.

Regulation and characteristics of vascular smooth muscle cell phenotypic diversity

“…Recently, TNF-α was shown to have a different effect on spindle-shaped versus epithelioid SMCs isolated from the human saphenous vein. 41 Whereas spindle-shaped SMCs showed increased proliferation after TNF-α treatment, epithelioid SMCs were induced to undergo apoptosis. Similarly, angiotensin II has been shown to induce apoptosis in epithelioid but not in spindle-shaped SMCs isolated from the rat aorta.…”

Potentially positive ageing-related variations of medial smooth muscle cells in the saphenous veins used as aortocoronary bypass grafts

“…First of all, a-actin immunostaining was employed to distinguish SMCs from the other cell types in the tunica media of the SV segments [12]. a-SM actin was previously detected in all stages of SMCs development [8]. We found that ageing of CABG patients had weak impact of a-SM actin immunostaining in the studied SMCs.…”

“…They also produce tissue inhibitors of metalloproteinases (TIMPs), and a balance between MMPs and TIMPs eventually determines the local homeostasis of the ECM [7]. Moreover, the population of venous SMCs was reported to be heterogeneous regarding metabolic, proliferative and chemotactic activities [8]. Subtypes of SMCs were characterized by altered expression of smooth muscle proteins such as a-smooth muscle actin (a-SM actin), smooth muscle myosin heavy chain (SM-MHC), calponin (CALP) and cytokeratin [8].…”

“…Moreover, the population of venous SMCs was reported to be heterogeneous regarding metabolic, proliferative and chemotactic activities [8]. Subtypes of SMCs were characterized by altered expression of smooth muscle proteins such as a-smooth muscle actin (a-SM actin), smooth muscle myosin heavy chain (SM-MHC), calponin (CALP) and cytokeratin [8]. These proteins were found to be associated with various stages of SMCs differentiation.…”

“…These proteins were found to be associated with various stages of SMCs differentiation. SM-MHC and CALP are expressed predominantly in the mature SMCs whereas CK-8 expression is typical for fetal and poorly differentiated cells [8,9].…”