Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies

Abstract

For patients with coronary artery disease or limb ischemia, placement of a vein graft as a conduit for a bypass is an important and generally durable strategy among the options for arterial reconstructive surgery. Vein grafts adapt to the arterial environment, and the limited formation of intimal hyperplasia in the vein graft wall is thought to be an important component of successful vein graft adaptation. However, it is also known that abnormal, or uncontrolled, adaptation may lead to abnormal vessel wall remodeling with excessive neointimal hyperplasia, and ultimately vein graft failure and clinical complications. Therefore, understanding the venous-specific pathophysiological and molecular mechanisms of vein graft adaptation are important for clinical vein graft management. Of particular importance, it is currently unknown whether there exist several specific distinct molecular differences in the venous mechanisms of adaptation that are distinct from arterial post-injury responses; in particular, the participation of the venous determinant Eph-B4 and the vascular protective molecule Nogo-B may be involved in mechanisms of vessel remodeling specific to the vein. This review describes (1) venous biology from embryonic development to the mature quiescent state, (2) sequential pathologies of vein graft neointima formation, and (3) novel candidates for strategies of vein graft management. Scientific inquiry into venous-specific adaptation mechanisms will ultimately provide improvements in vein graft clinical outcomes.

Fig 1

Mechanisms of arterial and venous determination during development of the embryonic vasculature. A) In arterial endothelial cells, Sonic hedgehog induces vascular endothelial growth factor (VEGF), which in turn activates Delta-Notch signaling. This cascade induces expression of the arterial-specific marker Ephrin-B2, and simultaneously limits expression of the venous-specific marker Eph-B4. B) In venous endothelial cells, COUP-TFII actively blocks expression of the VEGF receptor, and subsequently expression of the Delta-Notch cascade. The failure of this cascade prevents expression of Ephrin-B2 while simultaneously stimulates Eph-B4 expression.

Fig 2

Morphological and physiological features in an artery and a vein. IEL, Internal elastic lamina; EEL, External elastic lamina.

Fig 3

Time-course of vein graft neointimal formation. EC, endothelial cell; SMC, smooth muscle cell; MMP, matrix metalloproteinase; ECM, extracellular matrix.