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Granger DN, Senchenkova E. Inflammation and the Microcirculation. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.
While capillary growth and proliferation are rarely observed in normal adult tissues except during wound healing and cyclical events in the female reproductive cycle (ovulation, menstruation), with appropriate stimuli, the process of angiogenesis (development of new blood vessels from an existing vascular network) can be initiated (Figure 6.1). ECs exposed to such stimuli first detach from each other through alterations in adherens junction complexes, and metalloproteinases are then released to degrade the underlying basement membrane and surrounding structural elements. Hence, the initiation of angiogenesis is often associated with an increased capillary permeability that serves to enrich the adjacent interstitial compartment with plasma components. Upon destabilization of the endothelial cell monolayer, the cells then migrate (haptotaxis) toward the angiogenic stimulus within the extravascular space via integrin (avβ3, avβ5)-mediated adhesion to matrix proteins, with a concomitant proliferation of the ECs lining the vessel wall to replace the previously migrated cells. The migrating and proliferating ECs form cord-like structures in target tissues that later canalize to form functional vessels, which are further stabilized by surrounding pericytes. Tight cell–cell adhesion results from the expression and function of different adhesion molecules such as PECAM-1 and VE cadherin [92–94].
FIGURE 6.1
Events associated with inflammation-induced angiogenesis. During inflammation, angiogenesis is initiated by the activation of different cell populations, which release a variety of angiogenic factors. The next stage (proliferation/invasion) involves changes (more...)
6.1. Relevance To Inflammation
While angiogenesis is normally a tightly controlled process that rarely occurs in the adult organism, a number of pathological conditions are known to be associated with aberrant angiogenesis. These conditions include cancer, diabetic retinopathy, ischemic cardiovascular diseases (e.g., stroke), and chronic inflammatory diseases (e.g., IBD). Although the link between angiogenesis and inflammation has received much attention in recent years, there has long been evidence suggesting that these are two closely related processes. These include the appearance of newly formed blood vessels in granulation tissue, and the dual functionality of angiogenic factors, i.e., they exhibit both pro-inflammatory and pro-angiogenic effects. It should be emphasized that while inflammation and angiogenesis are capable of potentiating each other, these processes are distinct and separable. Nonetheless, there is growing evidence that the angiogenesis that accompanies chronic inflammation tends to prolong and intensify the inflammatory response. This contention is supported by reports describing a worsening of disease activity, tissue injury, and colonic inflammation in experimental IBD by administration or genetic overexpression of VEGF-A while treatment of colitic mice with anti-angiogenic agents or genetic overexpression of soluble VEGFR-1 had the opposite effect. These findings have led to the proposed use of anti-angiogenesis drugs in the treatment of IBD [92,95–104].
6.2. Mediators Of The Angiogenic Response
There is an abundance of factors produced by mammalian tissues that are capable of inhibiting or promoting blood vessel proliferation (Figure 6.1). Hence, the balance between these angiogenic and angiostatic factors determines the existence and rate of blood vessel proliferation in a tissue. In inflammation, this balance is clearly tipped in favor of angiogenesis. This response results, in part, because an inflammatory locus is often hypoxic and hypoxia is an important pro-angiogenic signal that activates the hypoxia-inducible factor signaling pathway, which elicits the transcription-dependent production of VEGF and FGF. Inflammation is also associated with the recruitment of circulating leukocytes and platelets, and the activation of resident macrophages, mast cells, and fibroblasts, all of which are capable to producing large quantities of pro-angiogenic factors, including VEGF and cytokines [93,94,97].
6.2.1. Vascular Endothelial Cell Growth Factor
The VEGF family and its receptors (VEGFR-1 and VEGFR-2) have long been implicated as a central figure in the regulation of angiogenesis. VEGF-A directly stimulates EC proliferation by engaging with the VEGFR-2 to activate tyrosine kinase and initiate the sprouting of new vessels from existing microvessels. Sprouting requires the destabilization of existing microvessels, which includes pericyte dropout, diminished cell–cell adhesion, and dissolution of the basement membrane. This process begins with an endothelial (“tip”) cell leaving the endothelial monolayer, penetrating the basement membrane, and invading the adjacent interstitial compartment. The tip cell assumes a distinct phenotype that enables it to produce lamellopodia that extend ahead of the cell to “taste” the environment and determine the appropriate migratory direction. Following the tip cell are migratory/proliferative cells (“trunk” or “stalk” cells), which allow for extension of the sprouting vessel and lumen formation. VEGF appears to mediate several steps in this process of sprout formation, including pericyte dropout, induction of tip cell migration, and the formation of lamellipodia, and to provide a substrate for tip cell chemotaxis in the interstitium. VEGF also diminishes the intensity of the endothelial cell–cell interactions in the angiogenic sprout by promoting the phosphorylation and internalization of VE-cadherin. The weakened cell–cell adhesion enables tip cells to depart from the endothelial lining and also accounts for the increased vascular permeability that is characteristic of proliferating blood vessels. While most of the angiogenic effects of VEGF are mediated through VEGFR-2, the hyperpermeability associated with this process requires the activation of both VEGFR-1 and VEGFR-2. Finally, it is noteworthy, in view of recent evidence implicating bone marrow-derived cells in the formation of new blood vessels in chronic inflammatory diseases, that VEGF may also contribute to the angiogenic process by mobilizing endothelial progenitor cells and other myeloid cells to the site of angiogenesis [94,100,104–107].
6.2.2. Cytokines and Chemokines
Infiltrating and resident inflammatory cells, ECs, and VSM all have the capacity to generate large amounts of cytokines and chemokines. Some of these substances exert significant pro-angiogenic or anti-angiogenic properties that may influence the intensity of the angiogenic response elicited during inflammation. Some of the effects on angiogenesis that are attributable to cytokines relate to their ability to prime ECs for the subsequent actions of VEGF. For example, TNF-α has been implicated in the priming of endothelial “tip cells” for migration induced by VEGF, an action that relates to the initial inhibition of VEGFR signaling induction of the “tip cell” phenotype. A more direct and potent action on angiogenesis is noted for the CXC family of chemokines with the glutamic acid–leucine–arginine (ELR) motif immediately proximal to the CXC sequence. The ELR-positive CXC chemokines, including CXCL-2 and IL-8/CXCL8, promote angiogenesis, while ELR-negative CXC chemokines, such as CXCL-9 and CXCL-10, are angiostatic. The primary receptor for chemokine-mediated angiogenesis is CXCR2, which is expressed, along with CXCR1, on ECs. This is supported by the observation that CXCR2 knockout mice and WT mice treated with CXCR2 neutralizing antibodies exhibit a blunted CXC chemokine-mediated angiogenic response. Members of the CC chemokine family that are also pro-angiogenic include, CCL2, CCL11, and CCL16. The engagement of CCL2 with its receptor (CCR2) on EC elicits chemotaxis and tube formation in vitro, and the chemokine has been shown to promote angiogenesis in vivo. CCL2 as well as IL-8 can mediate the homing of circulating endothelial progenitor cells to sites of inflammation. Finally, CCL2-induced angiogenesis has been associated with the induction of VEGF-A gene expression, suggesting that the chemokine works in concert with VEGF to promote angiogenesis during inflammation [94,96,108–110].
6.2.3. Reactive Oxygen and Nitrogen Species
Angiogenesis involves the activation of a variety of signaling pathways. While VEGF and cytokines/chemokines can stimulate different components in the angiogenesis process through different signaling pathways, the balance between NO and ROS production appears to be an important modulator of the angiogenic response to inflammation. VEGF and many cytokines are known to activate NADPH oxidase in vascular EC, likely as a result of the activation and translocation of the small GTPase Rac1 into the plasma membrane. There is also evidence that VEGF elicits the activation of eNOS, which is largely localized in caveolae, via a PI3K /Akt-dependent mechanism. NADPH oxidase-dependent ROS and eNOS-dependent signaling appear to influence different components of new vessel formation, including endothelial junction destabilization, MMP activation, EC migration, and tube formation. The importance of eNOS localization to EC calveolae is evidenced by the observation that caveolae-deficient ECs cannot migrate. The relevance of this observation to inflammatory disease is highlighted by studies demonstrating that caveolin (Cav-1)-deficient mice or WT mice treated with a Cav-1 inhibitory peptide exhibit a blunted angiogenic response to colonic inflammation. Mice that overexpress Cav-1 only in the endothelium also respond to inflammation in a manner consistent with endothelial Cav-1 as an important mediator of angiogenesis in experimental colitis. It remains unclear, however, whether the contribution of caveolae to inflammation-induced angiogenesis is related entirely or in part to localized production of NO and/or ROS [111–114].
6.3. Lymphangiogenesis
The enhanced vascular proliferation that accompanies inflammation is not limited to blood vessels. There is growing evidence for an increased abundance of lymphatic capillaries in inflamed tissues. Both acute inflammatory stimuli (e.g., bacterial infection) or chronic inflammatory diseases (e.g., human IBD) are associated with lymphangiogenesis. It has been proposed that failure of lymphatic pumping caused by a direct action of inflammatory mediators, such as prostaglandins (PGE2 PGI2) or cytokines, may lead to lymphatic insufficiency and a compensatory proliferative response. Alternatively, the lymphangiogenesis may result from a stimulatory action (mediated via NFkB) of cytokines such as TNF-α on different cells that produce and release of VEGF-C, a potent stimulant of lymphatic proliferation. Activated macrophages and granulocytes, which produce large amounts of VEGF-C and VEGF-D, have also been implicated in the lymphangiogenic response to inflammation. A role for VEGF-C in this response is supported by studies demonstrating that VEGFR-3-Ig ligand trap, which blocks VEGF-C and VEGF-D, suppresses the inflammation-induced lymphangiogenesis. Blocking integrin α5β1 signaling with small-molecule inhibitors also inhibits the lymph vessel proliferation associated with inflammation, presumably by directly inhibiting lymphatic endothelial cell proliferation and migration. The participation of soluble factors in this response is evidenced by the fact that lymphatic vessel proliferation also occurs in lymph nodes that perfused by lymph that drains the inflamed tissue. While the pathophysiological consequences of inflammation-induced lymphangiogenesis remain unclear, it has been suggested that the response helps to rid the inflamed tissue of edema fluid and it may facilitate the clearance of immune cells (macrophages, dendritic cells) from the tissue. This contention is supported by studies demonstrating that inhibition of inflammation-associated lymphangiogenesis increases the severity of the inflammatory cell accumulation and interstitial edema [115–119].
- Angiogenesis - Inflammation and the MicrocirculationAngiogenesis - Inflammation and the Microcirculation
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