Arteriogenesis, the good and bad of it.

Abstract

Arteriolar vessels that interconnect adjacent vascular territories in the form of networks or arcades exist normally in the skeletal [1] and cardiac muscle [2] of most mammals including man. They function usually as a means of efficient flow distribution, to act as capacitors for blood displacement in non-synchronously contracting muscles or are just remnants of the embryonic vascular network that has not fully reached its full determination. These vessels can expand by growth when pressure gradients develop, the most likely cause of which is the unilateral fall in pressure by a stenosis or occlusion of one of the arteries that feed into the network [2]. Although total blood flow into the network is now reduced (or unaltered due to compensating vasodilation) the velocity of blood flow in the vessels representing the shortest connection to the distal distribution of the occluded vessel is markedly increased. This creates an increase in the fluid shear stress [3] in the shortest pathway within the network which activates the endothelium. Activated endothelium has a typical synthetic and proliferative phenotype (increased endoplasmic reticulum, free ribosomes, loss of volume control, swelling) and is characterized by upregulation of adhesion molecules [2] and of monocyte chemoattractant protein (MCP-1) [4]. As a result of activation, monocytes adhere to the endothelium, become activated themselves and produce TNF-alpha and several other growth factors, cytokines and chemokines [5,6]. This starts the vascular growth which begins with endothelial proliferation which is soon followed by that of smooth muscle. Parallel with proliferation, or maybe preceding it, proteolytic activity starts to create the space for the expanding vessel and to remodel the given structures of the vessel itself [7]. This begins with the digestion of the internal elastic lamina, and the lysis of the extracellular matrix which enables the smooth muscle layers … * Corresponding author. Tel.: +49-6032-705-402; fax: +49-6032-705-419 w.schaper{at}kerckhoff.mpg.de