|
In some vascular provinces (femoral artery) acute occlusions are tolerated without necrosis due to the presence of an arteriolar network of collateral vessels which expands by growth after the occlusion. In most other vascular regions (heart, brain, kidney) a slowly progressing stenosis triggers collateral artery growth (arteriogenesis) to such an extent that final complete occlusion is also tolerated without tissue loss. The primary stimulus for arteriogenesis is fluid shear stress. Arterial occlusion in the presence of an arteriolar interconnecting network reduces the pressure in the distal stump and increases the pressure gradient along the collateral path, increases the blood flow velocity and shear stress, which in turn activates endothelium that increases the expression of adhesion molecules leading to monocyte adhesion. Monocytes provide the proteolytic enzymes and the growth factors necessary for the remodelling of the arteriole into an artery. A 20-fold increase of arterial diameter occurs in larger mammals including man. Growth stops when the fluid shear stress had normalized which is premature because only less than 50% of the conductance of the normal artery are finally reached by arteriogenesis. In contrast to angiogenesis, the sprouting or enlargement of pre-existent capillaries, hypoxia is not the governing factor in arteriogenesis. No hif-dependent growth factor is produced during arteriogenesis neither in the growing arterial tissue nor in the tissue surrounding it. The role of the monocyte in arteriogenesis is highlighted by the fact that eliminating them with phophonate-laden liposomes stops arteriogenesis as does treatment with 5fluorouracil and that femoral artery ligation during the rebound after 5fluoro accelerates arteriogenesis. When MCP-1, the strongest arteriogenic factor known (upregulated by shear stressed endothelium), is blocked by targeted disruption of its receptor (CCR2) gene, arteriogenesis is strongly inhibited. The presence of a persisting arteriolar network (remnant of the primary capillary network of embryonal development) is genetically determined and inherited: inbred mouse strains can exhibit a fully functional adult collateral network that is able to compensate for an acute occlusion without necrosis (Cl57/Bl6) or they cannot (BalbC) because of the presence or absence of an interconnecting arteriolar network. No amount of angiogenesis can compensate for the loss of an artery.
|