Marvels, mysteries, and misconceptions of vascular compensation to peripheral artery occlusion

Abstract

Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation.

Figure 1

Angiograms of human lower extremities with arterial occlusion demonstrate that major collaterals arise from pre-existing, named arteries as labeled. Collateral vessels are observed bypassing the site of a superficial femoral artery (SFA) occlusion (A), a popliteal artery occlusion (B), and multiple SFA occlusions (C & D) in three different patients. The occlusion sites are bounded by asterisks. Collateral vessels are identified by arrows and arrowheads with arrowheads denoting regions of greater tortuosity. Note that not all collaterals exhibit significant tortuosity. This demonstration of collateral development from pre-existing small arteries is consistent with reports of the pre-existing collateral circulation published in human anatomy texts since 1918 and in surgery texts and reviews of the human collateral circulation as cited in the text.

Figure 2

Representative porcine hindlimb angiograms demonstrate major collateral arteries develop from pre-existing small arteries. Studies were performed in 12 adult male Ossabaw miniature swine 4 weeks after ligation of the left superficial femoral artery (SFA). Asterisks in the left panel mark the occluded region in the experimental limb. The angiogram demonstrates that major bypass collaterals, identified by arrowheads, bridge from the gluteal artery (GA) and profunda femoral artery (PFA; deep femoral artery) to reconstitute the distal SFA. Angiograms were reviewed frame by frame to verify that the identified collaterals were responsible for the reconstitution of the distal SFA. Arrowheads in the right panel from a non-occluded control limb demonstrate the pre-existence of collateral paths shown in the left panel. While the center portion of the GA-SFA anastomosis is not seen in the angiogram, its presence was confirmed by dissection. The collateral branches originating from the gluteal artery consistently formed the largest collaterals reconstituting the SFA. An important role for the GA is consistent with the known pre-existing collateral circulation in humans in which the gluteal artery forms major arterial anastomoses [11]. The average diameter of the collaterals at the mid-zone region was 1.1 ± 0.1 mm, versus an average diameter of 3.6 mm for the profunda and 4.9 mm for the common femoral artery. Spatial calibration is identical for both panels.

Figure 3

Representative published angiograms (used by permission) identify major collateral pathways in the rat hindlimb after femoral artery ligation and demonstrate their pre-existence in control limbs [43,67]. The pathway in the upper set of angiograms [43] involves the perforating artery which connects distally to the popliteal artery. It is initially a major collateral pathway but undergoes regression after 7 days [43]. The lower angiogram [67] shows a more proximal pathway branching into the distal femoral artery. Arrows and arrowheads identify the collateral pathways in the experimental limb and show their pre-existence in the control limbs. The white arrows labeled SCI are added to the images and identify the superficial circumflex iliac artery, which provides a collateral pathway in rats ([55] and Figures 6 and 7) and is a major collateral in other species including humans [34].

Figure 4

Micrographs from Distasi et al. [24] (used by permission) demonstrate various major collateral pathways in the mouse hindlimb after femoral artery ligation or excision. Vascular casts were made with Microfil after perfusion fixation. For each enlarged collateral path, pre-existing vessels were present in the contralateral control limb as shown in A. Panel B depicts the four major collateral pathways. II, internal iliac artery; FA, femoral artery; PF, profunda femoral artery; S, saphenous artery; P, popliteal artery.

Figure 5

Resistances of the collateral circulation and distal microvasculature after rat femoral artery ligation. The data shown are from Unthank et al. [53,98] for rats and are consistent with other studies in rats [34,106] and cats [73]. The composite data indicate that even after the initial collateral dilation following acute femoral artery occlusion, collateral resistance is 70–80% of the total resistance to the collateral dependent tissue and can decrease by ~70% within weeks. During the same time, no significant decrease in microvascular resistance is observed.

Figure 6

Select enlargement of pre-existing collateral pathways. Both the superficial circumflex iliac (SCI) artery and perforating artery form collateral pathways in the rat after femoral artery ligation. We compared the diameters of both at 2 weeks post-ligation. Collateral paths were established by tissue dissection after perfusion fixation and Microfil casting. The major branch of the SCI and the perforating artery were isolated and diameters determined from cross-sections. The branch of the SCI was significantly enlarged in the experimental limb (>60%) as shown above. In contrast, the perforating artery was enlarged in only three of 12 rats and was reduced in diameter in the remainder (119 ± 20 experimental vs. 237 ± 12 μm control limb, P < 0.001), consistent with the regression previously reported to occur after 1 week [43]. The consistent enlargement of the smaller SCI branch presumably occurs because it provides a shorter path with less resistance than the perforating artery. With enlargement of the SCI branch, blood flow and shear stress are likely reduced in the perforating artery which then undergoes regression (flow-mediated inward remodeling). The decrease in perforating artery diameter is consistent with Schoops observation of the regression of long collaterals in humans [80].

Figure 7

Cross-sections of major collateral arteries and their controls from miniature pig, rat, and mouse after femoral artery ligation. (A) Comparison of control and collateral porcine arteries demonstrate a remarkable increase in intimal cell number in the collateral. This is characteristic of arteries undergoing flow-mediated outward remodeling and occurs without neointima formation. The same result was observed for the major collaterals in rats (B, branch from superficial circumflex iliac artery) and mice (D). For a regressing collateral pathway identified in the rat (C, perforating artery), neointimal formation (arrow) is apparent, but not an increase in intimal cell number. (E) Images of a mouse and rat collateral are inserted into the lumen of a pig collateral to emphasize the tremendous difference (>10-fold) in vessel size, wall thickness, and distance from inner to outer wall layers. Ad, adventitia; M, media; L, lumen; arrowheads indicate the intima, asterisks denote remnants of Microfil® casting agent in the lumen. Control and collateral artery pairs from all species were imaged at the same magnification.