Trying to make sense of a cluster of chronic illnesses: Part 2

In this post, I will share the questions I asked as I fell further into my online research rabbit hole last night and the URLs of the articles I found. The reason for explaining this further is to leave a trail of breadcrumbs to anyone more knowledgeable than me who wants to retrace my journey.

It is technical and some of the quoted text is a painful stretch for my understanding.  My hope is there is someone out there who can help me make sense of all of this.

Looking for things in common

As I mentioned in my last post, my online search began with a question concerning whether or not smooth muscle cells exist in the human retina.  

I learned that smooth muscle cells and pericytes form the underpinnings of vascular structures throughout the body. (reference) Pericytes exist in the retina and express alpha-smooth muscle actin. (reference) The highest density of pericytes in the body is found in vessels of the neural tissues, such as the brain and the retinas. (reference) Pericytes are also the progenitors of coronary artery smooth muscle (reference) 

Pericytes

I then wanted to learn about the role of pericytes in creating and maintaining blood vessels.

Pericytes are the likely cell of origin for a group of mesenchymal tumors with a common perivascular growth pattern...and include...angioleiomyoma... (reference)  

Blood vessels are composed of two interacting cell types. Endothelial cells form the inner lining of the vessel wall, and perivascular cells—referred to as pericytes, vascular smooth muscle cells or mural cells—envelop the surface of the vascular tube. Over the last decades, studies of blood vessels have concentrated mainly on the endothelial cell component, especially when the first angiogenic factors were discovered, while the interest in pericytes has lagged behind. Pericytes are, however, functionally significant; when vessels lose pericytes, they become hemorrhagic and hyperdilated, which leads to conditions such as edema, diabetic retinopathy, and even embryonic lethality. Recently, pericytes have gained new attention as functional and critical contributors to tumor angiogenesis and therefore as potential new targets for antiangiogenic therapies. Pericytes are complex. Their ontogeny is not completely understood, and they perform various functions throughout the body. This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.   (reference)

Capillary pericytes are contractile and play a crucial role in the regulation of microcirculation.  However, failure to detect components of the contractile apparatus in capillary  pericytes, most notably alpha-smooth muscle actin, has questioned these findings. Using strategies that allow rapid filamentous-actin (F-actin) fixation (i.e. snap freeze fixation with methanol at −20°C) or prevent F-actin depolymerization (i.e. with F-actin stabilizing agents), we demonstrate that pericytes on mouse retinal capillaries, including those in intermediate and deeper plexus, express α-SMA. Junctional pericytes were more frequently α-SMA-positive relative to pericytes on linear capillary segments. Intravitreal administration of short interfering RNA (α-SMA-siRNA) suppressed α-SMA expression preferentially in high order branch capillary pericytes, confirming the existence of a smaller pool of α-SMA in distal capillary pericytes that is quickly lost by depolymerization. We conclude that capillary pericytes do express α-SMA, which rapidly depolymerizes during tissue fixation thus evading detection by immunolabeling. (reference)

In the early stages of angiogenesis, pericytes induce endothelial cells to form correct vessels and in t he later stages they inhibit endothelial growth and mediate the maturation of blood vessels and strengthen the capillary barriers. (reference)

Angiogenesis

Since the vascular system was wrapped up in many of my conditions, angiogenesis was the next topic of inquiry.

Angiogenesis is the process that forms new capillaries out of existing blood vessels in your body. These blood vessels are lined with endothelial cells which move and grow in number to allow the new capillaries to form. (reference) 

Abstract: Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.  (reference)

Imbalanced angiogenesis contributes to many diseases.  For example, changes in angiogenesis have been implicated in the pathophysiology of rosacea. 

What is the role of pericytes in angiogenesis?

Abstract: Pericytes are branched cells embedded within the basement membrane of capillaries and post-capillary venules. They provide an incomplete investment to endothelial cells, thus reinforcing vascular structure and regulating microvascular blood flow. Pericytes exert an important role on endothelial cell proliferation, migration and stabilization. Endothelial cells, in turn, stimulate expansion and activation of the pericyte precursor cell population. The balance between the number of endothelial cells and pericytes is highly controlled by a series of signaling pathway mechanisms operating in an autocrine and/or paracrine manner. In this review, we will first examine the molecular aspects of the pericyte activating factors secreted by endothelial cells, such as platelet derived growth factor B (PDGF-B), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β) and angiopoietins (Angs), as well as signaling pathways involving Notch and ephrins. We will then consider the complex and multivarious contribution of pericytes to the different aspects of angiogenesis with particular emphasis on the potential role of these cells as targets in tumor therapy.  (reference)

What is VEGF and what is its role in angiogenesis?

VEGF stands for vascular endothelial growth factor. It is a potent mediator of vascular permeability and inflammation that might play a role in the pathogenesis of rosacea. VEGF is the most essential positive regulator of pathological angiogenesis and increased vascular permeability in patients with inflammatory diseases and tumors. Although the published literature includes numerous studies on the role of vascular changes and inflammation in the pathogenesis of rosacea, onloy a few have investigated the role of VEGF. (reference) 

VEGF - D is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). (reference)

VEGF is an important angiogenic factor reported to induce migration and proliferation of endothelial cells, enhance vascular permeability, and modulate thrombogenicity. (reference)

VEGF activates endothelial cells to proliferate and migrate, subsequently resulting in new tube formation and blood flow. Pericytes regulates the proliferation, migration and stabilization of endothelial cells within angiogenesis.

Pathological angiogenesis, which is mainly induced through VEGF and their receptors, is involved in many vision impairing ocular disorders such as corneal neovascularization. (reference) 

In the retina, VEGF expression is localized in the ganglion, inner nuclear, and RPE cell layers. VEGF is crucial for cellular homeostasis as a neurotrophic and cell survival factor but it is also one of the critical mediators of pathological neovascularization [12]. Intraocular VEGF is upregulated by hypoxia and inflammation (Figure 1). Upregulated VEGF drives neovascularization and increases vascular permeability. This leads to different complications such as leaky vessels, retinal detachment, fibrovascular proliferation, retinal exudation, edema, and ultimately photoreceptor neuron death and blindness. Pathological angiogenesis in the eye includes many diseases—for example, AMD, DR, retinopathy of prematurity (ROP), and corneal neovascularization [13].

The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality...Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted. (reference)

What are vasa vasorum?

Vasa vasorum (VV) are a specialized microvasculature that play a major role in normal vessel wall biology and pathology. (reference)

The present study shows that patients with a history of SCAD have a higher density of coronary adventitial VV in nonculprit segments adjacent to the SCAD region. A previous study found that neoangiogenesis of capillary vessels branching from the VV in the adventitia and leakage of neoangiogenetic capillaries is one mechanism of spontaneous cervical artery dissection (3). In the present study, we made a similar observation of extensive proliferation of adventitial VV in patients with SCAD. This finding supports a common intramural hematoma/atypical dissection predisposition in adventitial VV that extends to patients with SCAD. Extravasation of blood from proliferative adventitial VV may lead to the formation of microhematoma between media and adventitia that could result in coronary dissection. However, the present study does not provide a causal relationship between SCAD and increased VV density, which may be reactive.

In conclusion, the present study demonstrated that the adventitial VV is increased in patients with SCAD and suggested that proliferation of adventitial VV may be linked to development of SCAD in humans. Further studies are needed to determine the causal relationship between VV and SCAD.

The journey so far

By this time is was the middle of the night and my eyes were feeling the strain, so I stopped there, for now.

I had learned that pericytes and VEGF play a huge role in angiogenesis throughout the body. That most of the conditions I have (rosacea, congestive heart failure induced by SCADs, LAM, pulmonary emboli, retinoschisis) possibly have two factors in common:

1. VEGF dysfunction

2. Pathological angiogenesis

I feel I need to understand more about VEGF (since there are different varieties of this which may have different roles in angiogenesis).  I also want to do more research around psoriasis, recurrent corneal erosion and leukemia as other members of my family have/have had these. My guess is there may be some connection as well.  My working idea is that VEGF and the regulating pericytes may be at the root of my health conditions and theirs. If that is possible, then a genetic connection is also possible.

I'll keep you posted.