Spatial and temporal coordination of bone marrow-derived cell activity during arteriogenesis: regulation of the endogenous response and therapeutic implications

Abstract

Arterial occlusive disease is the leading cause of morbidity and mortality throughout the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating arterial occlusive disease has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here, we present the evidence suggesting roles for multiple BMC populations-from neutrophils and mast cells to progenitor cells-and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development.

Figure 1

The stages of arteriogenesis can be broken down into three phases (initiation, growth, and maturation). A) The drop in perfusion pressure distal to an occlusion causes increased flow through pre-existing collateral arteries. The increased shear stress triggers an inflammatory response in endothelial cells (ECs, blue, activation indicated by orange) initiating bone marrow derived cell (BMC) recruitment through expression of adhesion molecules and chemokines. B) During the initiation phase, the recruitment of early BMCs (light green) such as neutrophils (PMNs) aid the breakdown of the extracellular matrix (ECM) and basement membrane (BM). Paracrine and autocrine signaling through cytokines and growth factors (GFs) leads to smooth muscle cell (SMC) differentiation into a synthetic phenotype (indicated by grey) to allow for migration, proliferation, and the creation of a transitional matrix. C) Later arriving BMCs (dark green), such as monocytes, further stimulate SMC and EC proliferation and outward growth through paracrine support and matrix remodeling during the growth phase. This leads to lumenal expansion and vessel lengthening in a tortuous pattern, characteristic of growing collateral vessels. As lumenal diameter increases, resistance decreases, distal perfusion is restored, and shear stress begins to normalize. This leads to the resolution of endothelial cell inflammation. D) As inflammation decreases, BMCs disappear and proliferation wanes. Collateral vessels then undergo one of two paths. Vessels with the least resistance supply the most blood flow and mature into the dominant collaterals. Small collateral vessels that cannot maintain sufficient hemodynamic stimulus undergo neointimal hyperplasia and eventual regression.

Figure 2

Time line of recruitment of leukocyte subsets during arteriogenesis. The earliest responding leukocytes appear to be neutrophils followed by inflammatory monocytes and mast cells. The temporal recruitment pattern suggests possible relationships between the recruitment of other leukocyte populations. The timing of progenitor cell recruitment, however, is largely unknown. It is important to note that the sequence of leukocyte recruitment and feedback appears to take place within the first few hours and days after the initiation of collateral vessel development. An approximate timeline is given based on BMC recruitment to collateral vessels after femoral arterial ligation.

Figure 3

Proposed interconnected relationships of recruitment between BMC populations. Many BMC populations may aid arteriogenesis through the activation and subsequent recruitment of inflammatory monocytes. However, the disruption in earlier BMC recruitment may amplify collateral growth impairments through the reduced recruitment and synergistic activation of other, later-arising BMC populations. How and if bone marrow-derived progenitor cells influence the recruitment of other BMC populations is still largely unknown.