Collateral circulation: past and present

Abstract

Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.

Figures

Fig. 1

Network analysis of differentially expressed proteins (red symbols) involved in arteriogenesis. We performed a literature scan (Pathway Studio) in order to retrieve an extract of regulatory and interaction pathways. Different ligands and receptors act in concert leading to an activation of a variety of transcription factors and signalling pathways via the central players calcium and NO. Bold arrows indicate a fluid shear stress activated new pathway, which resulted from the molecular investigation of the shunt model. (FSS fluid shear stress, MCP-1 monocyte chemo-attractant protein, Dll1 delta-like1, JAG1 jagged1, VEGF vascular endothelial growth factor, FN1 fibronectin, Trpv4 transient receptor potential cation channel, subfamily V, member 4, NOS1 neuronal nitric oxide synthase, NOS2A inducible nitric oxide synthase, NOS3 endothelial nitric oxide synthase, ITGA5: αVβ3 Integrin, EFNB2 Ephrin B2, NO nitric oxide, KLF2 Krueppel-like factor2, SRF serum response factor, EGR1 early growth response1, RHOA ras homolog gene family, member A, CFL1 cofilin1, Abra actin binding Rho activator, Dream DRE antagonist modulator, TMSB4X thymosinβ4, Dstn destrin)