Abstract
Exposing a vein to altered hemodynamics by creating an arteriovenous (AV) shunt evokes considerable vessel formation that may be of therapeutic potential. However, it is unclear whether the introduction of oscillatory flow and/or flow increase is decisive. To distinguish between these mechanical stimuli we grafted a femoral vein into the arterial flow pathway of the contralateral limb in rats creating an arterioarterial (AA) loop (n = 7). Alternatively, we connected the femoral artery and vein using the vein graft, whereby we created an AV-loop (n = 27). Vessel loops were embedded in a fibrin filled chamber and blood flow was measured by means of flow probes immediately after surgery (day 0) and 15 days after loop creation. On day 15, animals were sacrificed and angiogenesis was evaluated using μCT and histological analysis. Mean flow increased from 0.5 to 2.4 mL/min and was elevated throughout the cardiac cycle at day 0 in AV-loops whereas, as expected, it remained unchanged in AA-loops. Flow in AV-loops decreased with time, and was at day 15 not different from untreated femoral vessels or AA-loop grafts. Pulsatile flow oscillations were similar in AV-and AA-loops at day 0. The flow amplitude amounted to ~1.3 mL/min which was comparable to values in untreated arteries. Flow amplitude remained constant in AA-loops, whereas it decreased in AV-loops (day 15: 0.4 mL/min). A large number of newly formed vessels were present in AV-loops at day 15 arising from the grafted vein. In marked contrast, angiogenesis originating from the grafted vein was absent in AA-loops. We conclude that exposure to substantially increased flow is required to initiate angiogenesis in grafted veins, whereas selective enhancement of pulsatile flow is unable to do so. This suggests that indeed flow and most likely wall shear stress is decisive to initiate formation of vessels in this hemodynamically driven angiogenesis model.
Highlights
Hemodynamic forces are important regulators for maintenance, growth and regression of the vascular network [1]
In vivo studies that were focused on embryonic vessel formation revealed that vessels with high blood flow exhibit few or no tip cells and that an increase of flow is accompanied by an induction of splitting angiogenesis, so called intussusception [7,8]
At the time of explantation patency of the AV loop and absence of thrombosis was verified in all animals due to a successful perfusion of Ink-solution and / or via direct blood flow measurement using flow probes. 3 animals (n = 1 in AV, n = 2 in AA loop) exhibited no flow and ink staining was absent
Summary
Hemodynamic forces are important regulators for maintenance, growth and regression of the vascular network [1]. While many studies focused on these molecular processes and contributing transduction processes within the cell [4,5], less is known about the mechanical forces that induce angiogenesis. Most of these studies investigated vascular responses to altered hemodynamics, such as pulsatility or mechanical load, in vitro [6]. Pressure and oxygen were considered to be responsible for the maintenance of identity genes in developing arteries of the vascular plexus in the chicken embryo yolk sac [9]. Watson and colleagues demonstrated fundamental differences between hypoxia-driven and developmental angiogenesis in the developing zebrafish embryo and pointed out that blood flow is required for angiogenesis in response to hypoxic signaling but is not required for normal vessel patterning [12]
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