The life cycle of a capillary: Mechanisms of angiogenesis and rarefaction in microvascular physiology and pathologies

Abstract

Capillaries are the smallest blood vessels (<10 μm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in nutrient and gas exchange between blood and tissues. Capillary endothelial cells also produce vasoactive molecules and initiate the electrical signals that underlie functional hyperemia and neurovascular coupling. Accordingly, capillary function and density are critical for all cell types to match blood flow to cellular activity. This begins with the process of angiogenesis, when new capillary blood vessels emerge from pre-existing vessels, and ends with rarefaction, the loss of these microvascular structures. This review explores the mechanisms behind these processes, emphasizing their roles in various microvascular diseases and their impact on surrounding cells in health and disease. We discuss recent work on the mechanisms controlling endothelial cell proliferation, migration, and tube formation that underlie angiogenesis under physiological and pathological conditions. The mechanisms underlying functional and anatomical rarefaction and the role of pericytes in this process are also discussed. Based on this work, a model is proposed in which the balance of angiogenic and rarefaction signaling pathways in a particular tissue match microvascular density to the metabolic demands of the surrounding cells. This negative feedback loop becomes disrupted during microvascular rarefaction: angiogenic mechanisms are blunted, reactive oxygen species accumulate, capillary function declines and eventually, capillaries disappear. This, we propose, forms the foundation of the reciprocal relationship between vascular density, blood flow, and metabolic needs and functionality of nearby cells.

Keywords: Angiogenesis; Arteriogenesis; Heart failure with preserved ejection fraction; Hypertension; Microvascular rarefaction; Pericytes; Small vessel disease; Vascular dementia.

Fig. 1.

How a blood vessel is born. Cartoons depicting arteriogenesis and angiogenesis (A) as well as intussusceptive (B) and sprouting (C) angiogenesis.

Fig. 2.

The mechanism of arteriogenesis. The sequence of events underlying arteriogenesis (initiation (A), matrix degradation (B), growth (C), and maturation (D)), illustrated in cartoon form.

Fig. 3.

The mechanisms of angiogenesis. The sequence of events underlying angiogenesis (initiation (A), matrix degradation (B), growth (C), anastomosis (D), and maturation (E)), illustrated in cartoon form.

Fig. 4.

The functional consequences of vascular rarefaction in the brain. A healthy vascular supply (A) services metabolically active tissues and becomes strained during hypertension (B). Blood flow becomes dysregulated as vascular cells become damaged (C). Functional rarefaction occurs when capillaries no longer conduct blood flow (D). Tissues start to become dysfunctional as their metabolic requirements are no longer met. In anatomical rarefaction (E), capillaries begin to die and tissue function is severely blunted.

Fig. 5.

Endothelial dysfunction in vascular rarefaction. eNOS becomes downregulated, and increased ROS generation by AT₂R disables NO-induced vasodilation (A). Silencing of K⁺ and TRPV4 channels compromises endothelial cell-to-cell communication and vasoreactivity (B). PIP₂ depletion prohibits K_IR2.1 channel hyperpolarization, and AKAP5 expression declines, dispersing and blunting the cooperative gating of TRPV4 channels. Finally, endothelial trans- and paracellular permeability is regulated by attached pericytes (C). This becomes disrupted during VEGF-induced angiogenesis and AngII-induced rarefaction, where pericytes detach and die, respectively.

Fig. 6.

Proposed models of contractile cell dysfunction preceding rarefaction. During hypertension, SMCs become hypercontractile through several pathological processes (A). SR-PM domains break down, disrupting BK_Ca-RyR coupling. Functional BK_Ca channels are depleted, whilst Ca_V1.2 channels become hyperactive, increasing contractility. It is possible that K_V2.1 channels may also contribute to Ca_V1.2 super-clustering. In health, AngII-AT₁R signaling drives contractility and oxidative stress in SMCs and pericytes (B). In hypertension, overexpressed AT₁R increases SMC contractility and oxidative stress. This may be mirrored in pericytes and could initiate their loss in rarefaction. These proposed mechanisms could contribute to hypertrophic growth and microvascular pericyte death, which may exacerbate pre-existing endothelial dysfunction and permeability (C).