The Range of Adaptation by Collateral Vessels After Femoral Artery Occlusion

Abstract

Abstract-Natural adaptation to femoral artery occlusion in animals by collateral artery growth restores only Ϸ35% of adenosine-recruitable maximal conductance (C max ) probably because initially elevated fluid shear stress (FSS) quickly normalizes. We tested the hypothesis whether this deficit can be mended by artificially increasing FSS or whether anatomical restraints prevent complete restitution. We chronically increased FSS by draining the collateral flow directly into the venous system by a side-to-side anastomosis between the distal stump of the occluded femoral artery and the accompanying vein. After reclosure of the shunt collateral flow was measured at maximal vasodilatation. C max reached 100% already at day 7 and had, after 4 weeks, surpassed (2-fold) the C max of the normal vasculature before occlusion. Expression profiling showed upregulation of members of the Rho-pathway (RhoA, cofilin, focal adhesion kinase, vimentin) and the Rho-antagonist Fasudil markedly inhibited arteriogenesis. The activities of Ras and ERK-1,-2 were markedly increased in collateral vessels of the shunt experiment, and infusions of L-NAME and L-NNA strongly inhibited MAPK activity as well as shunt-induced arteriogenesis. Infusions of the peroxinitrite donor Sin-1 inhibited arteriogenesis. The radical scavengers urate, ebselen, SOD, and catalase had no effect. We conclude that increased FSS can overcome the anatomical restrictions of collateral arteries and is potentially able to completely restore maximal collateral conductance. Increased FSS activates the Ras-ERK-, the Rho-, and the NO-(but not the Akt-) pathway enabling collateral artery growth. Key Words: arteriogenesis Ⅲ fluid shear stress Ⅲ shunt Ⅲ growth factors Ⅲ microarrays T he restoration of maximal conductance (C max ) in animals after arterial occlusion remains defective (35% in the canine coronary circulation 1 and 40% in the rabbit hind limb 2 ) in spite of the fact that normal resting blood flow is reached early. As a consequence exercise testing in experimental animals reveals defects similar to those in human patients. 3 It was not known until now whether collateral vessels are potentially able to restore the full dilatory reserve of a normal vascular bed. Many observations would predict that this is not the case: the multitude of small vessels that replace an occluded artery is inefficient according to Poissieulle's Law, and the tortuosity of collateral vessels offers finite resistance because of curvature flow and increased collateral length. 4 One reason for the defective adaptation may lie in the fact that fluid shear stress normalizes prematurely: FSS falls by the third power of the growing radius. We tested the hypothesis whether a sustained increase of FSS is able to prolong the growth process and to restore normal maximal conductance. The method to achieve this was the creation of a shunt between the distal stump of the occluded femoral artery and the accompanying vein. 5 The novelty of the present findings is the demonstration that C max can be reach...

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

“…Outward collateral artery growth is therefore hypothesized to stop once normalization to the shear stress set point has been achieved 2, 3, 4, 5. Premature normalization to the shear stress set point has been a predominant rationalization for the failure of collateral arteries to realize full arteriogenic capacity, frequently reaching only 30% to 40% of the maximal conductance 74. However, our results indicate that shear stress actually remains elevated in collateral artery segments exhibiting limited arteriogenic capacity.…”

The role of blood flow and microRNAs in blood vessel development

“…It is established that arteriogenesis, the outward remodeling of preexisting arterioles (mainly in the proximal part of the network), and angiogenesis (mainly in the distal part of the network), contribute to restoring flow and oxygenation after an ischemic insult. Increased blood flow appears to be an essential trigger for the arteriogenesis response (Eitenmuller et al, 2006), while tissue ischemia associates with the magnitude of the angiogenic response. Interestingly, inhibition of the biogenesis of miRNAs results in a severely disturbed vascular adaptive response after arterial occlusion (Suarez et al, 2008).…”

Stimulierung des Wachstums peripherer und zerebraler Kollateralarterien zur Erhöhung der intravasalen Flussrate im Tiermodell

“…Jedoch ist das Kollateralarterienwachstum in vielen Fällen nicht ausreichend, um die bestehenden Stenosen oder Verschlüsse vollständig zu kompensieren. Aus Tier modellen wissen wir, dass durch das na türliche Wachstum von Kollateralarterien gerade einmal 40% der maximalen Kon duktanz der ursprünglichen Arterie er reicht werden [1,3]. Aus diesem Grund ist es ein wichtiges therapeutisches Ziel, nach Möglichkeiten zu suchen, das Wachstum von Kollateralarterien zu stimulieren und damit diesen natürlichen Prozess zu opti mieren.…”

“…In früheren Studien an einem Schweine und Kaninchenmodell konnte unsere Ar beitsgruppe zeigen, dass nach Femoralar terienligatur die Schubspannung die trei bende Kraft der peripheren Arteriogenese ist und dass durch eine langfristige Erhö hung der Schubspannung durch eine Ab leitung des Kollateralflusses in das Venen system im Sinne einer arteriovenösen Fis tel eine derartige Steigerung des Kollate ralarterienwachstums zu erreichen ist, dass die physiologische Funktion der ver schlossenen Arterie komplett wiederher gestellt werden kann [1,3] …”