Interdependence of Angiogenesis and Arteriogenesis in Development and Disease

Abstract

The structure of arterial networks is optimized to allow efficient flow delivery to metabolically active tissues. Optimization of flow delivery is a continuous process involving synchronization of the structure and function of the microcirculation with the upstream arterial network. Risk factors for ischemic cardiovascular diseases, such as diabetes mellitus and hyperlipidemia, adversely affect endothelial function, induce capillary regression, and disrupt the micro- to macrocirculation cross-talk. We provide evidence showing that this loss of synchronization reduces arterial collateral network recruitment upon arterial stenosis, and the long-term clinical outcome of current revascularization strategies in these patient cohorts. We describe mechanisms and signals contributing to synchronized growth of micro- and macrocirculation in development and upon ischemic challenges in the adult organism and identify potential therapeutic targets. We conclude that a long-term successful revascularization strategy should aim at both removing obstructions in the proximal part of the arterial tree and restoring "bottom-up" vascular communication.

Keywords: AAV; MRTF-A; Trio; angiogenesis; arteriogenesis; blood flow; endothelial cell shape; sFlt1; shear stress.

Figure 1

Schematic illustration of an arterial network indicated as electrical resistances coupled in series to a battery. In electrical terms: I (current) = V (voltage) divided by R (resistance), in biological terms Amount of Blood Flow = Pressure difference divided by Peripheral Resistance. The collateral arteries are upstream and coupled in series with the microcirculation. Therefore, changes in the resistance of the microcirculation affect the blood flow through the network. Lowering resistance R3 (microcirculation) will result in lower total resistance (Rt). As a consequence, at a given pressure difference (P), more flow will go through the arterial network. Subsequently, the upstream arterial collaterals (Resistance 1) will become exposed to more flow and shear stress levels, and increased shear stress stimulates outward lumen remodeling of collateral arteries. Diabetes and hypertension interfere with this feedback system.

Figure 2

Interdependence of arteriogenesis and angiogenesis in healthy and arteriosclerotic vessels. (A): Schematic representation of the arterial network. Arterial occlusion disrupts blood flow to the microcirculation. (B): In the presence of the proximal occlusion, stimulation of angiogenesis in the microcirculation will not result in restoring peripheral blood flow. (C): Restoring blood flow upon occlusion requires the recruitment of native collaterals or de novo formation of collaterals that can bypass the occlusion in the arterial network. (D): Schematic representation of the arterial network in the leg with native arterial collaterals. Flow distribution indicated by arrows. (E): Occlusion in the main feed artery results in rerouting of blood flow and flow driven outward remodeling of pre-existing native arterial collaterals (arrowheads). (F): Diabetes and hypertension associated with rarefaction of small arterioles and capillary networks (indicated in dark blue) and impaired (flow driven) outward lumen remodeling (arteriogenesis) of arterial collateral networks (impaired collaterals in grey). In this scenario, only targeting upstream collaterals is not sufficient to achieve increased oxygen and nutrient delivery to the periphery. The perfusion of the microcirculation needs to be improved as well.

Figure 2

Interdependence of arteriogenesis and angiogenesis in healthy and arteriosclerotic vessels. (A): Schematic representation of the arterial network. Arterial occlusion disrupts blood flow to the microcirculation. (B): In the presence of the proximal occlusion, stimulation of angiogenesis in the microcirculation will not result in restoring peripheral blood flow. (C): Restoring blood flow upon occlusion requires the recruitment of native collaterals or de novo formation of collaterals that can bypass the occlusion in the arterial network. (D): Schematic representation of the arterial network in the leg with native arterial collaterals. Flow distribution indicated by arrows. (E): Occlusion in the main feed artery results in rerouting of blood flow and flow driven outward remodeling of pre-existing native arterial collaterals (arrowheads). (F): Diabetes and hypertension associated with rarefaction of small arterioles and capillary networks (indicated in dark blue) and impaired (flow driven) outward lumen remodeling (arteriogenesis) of arterial collateral networks (impaired collaterals in grey). In this scenario, only targeting upstream collaterals is not sufficient to achieve increased oxygen and nutrient delivery to the periphery. The perfusion of the microcirculation needs to be improved as well.

Figure 3

Angiogenesis and arteriogenesis upon recombinant AAV (rAAV) encoding for Thymosin ß4 (Tß4). (A) Capillary/muscle fiber ratio (C/MF) after application of rAAVTß4 either whole limb (retrograde venous infusion) or lower limb (intramuscular injection) with or without L-NAME coapplication. (B) Collateral count (% of d7 level) at d28. Dotted lines are control group levels. For methods cf. [22].

Figure 4

Interdependence of micro- and macrovessel growth. Key mechanisms of vessel growth in developing and adult organisms include capillary formation and stabilization by pericytes (=maturation) as well as resistance control by newly added smooth muscle cells to arteriolar endothelial cells (arteriologenesis), e.g., via Notch signaling. These functional units feedback demand to existing conductance vessels, e.g., via nitric oxide-mediated vessel dilation and subsequent growth (=arteriogenesis).