Arterial dissections: Common features and new perspectives

Abstract

Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations - such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-β signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1, collagen genes, fibrillin and TGF-β receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state is lost and replaced by a proliferative activated phenotype. Of interest, dissections in various anatomical locations are associated with distinct sex and age predilections, suggesting involvement of gene and environment interactions in disease pathogenesis. Importantly, these cellular mechanisms are potentially therapeutically targetable. Consideration of arterial dissections as a collective pathology allows insight from the better characterized dissection types, such as that involving the thoracic aorta, to be leveraged to inform the less common forms of dissections, including the potential to apply known therapeutic interventions already clinically available for the former.

Keywords: TGF-β; aortic dissection; arterial dissection; cervical artery dissection (CeAD); endothelial cells (ECs); extracellular matrix; spontaneous coronary artery dissection (SCAD); vascular smooth muscle cells (VMSCs).

FIGURE 1

Arterial dissections are reported in large- and medium-sized arteries throughout the body at varying frequencies within the population. The risk of dissection varies with sex and age. Reported incidences correlate with average intimal medial thickness. Created with BioRender.com.

FIGURE 2

Typical architecture of medium to large, elastic and muscular arteries. Arteries comprise of three layers – the tunica intima is the innermost layer consisting of an endothelial monolayer; abluminal this monolayer is an ECM membrane located between the intima and the media, the latter being the second layer of the artery. The tunica media is concentrically layered with lamellar units of VSMCs bounded by elastin- and collagen-rich fibers. In larger arteries, the media is perfused by capillaries known as vasa vasorum, which enter the media through the outermost layer, the tunica adventitia; an ECM and fibroblast-rich layer. Created with BioRender.com.

FIGURE 3

Phenotypic changes in the cellular and extracellular components of the artery in response to injury/infection. Created with BioRender.com.

FIGURE 4

The two pathologies of arterial dissections: bleeding within the tunica media results in intramural hematoma formation with separation of the tunica media layer to create a false lumen that causes occlusion of the true lumen of the vessel, thereby preventing tissue perfusion. Some dissection events are associated with tunica intima tearing (intimal failure). Created with BioRender.com.

FIGURE 5

Risk profiles of pulmonary artery dissection patients. Like sufferers of aortic dissections, SCAD, and CeAD, pulmonary artery dissection occurrence varies with age and sex; data from (239).

FIGURE 6

Pathways perturbed in arterial dissections include the extracellular matrix (ECM), TGF-β, signaling, cellular contraction/cytoskeleton, and metabolism. Dysregulation in any number of these pathways can drive vascular smooth muscle cells (VSMCs) toward a more synthetic phenotype. Variants in the same genes (italicized in blue) belonging to these pathways have been commonly identified in at least two types of arterial dissections. Created with BioRender.com.

FIGURE 7

Proposed mechanism for arterial dissections. Atypical ECM deposition, activation of VSMC or EC will perturb vasa vasorum (VV) blood flow, leading to either their spontaneous rupture, or an area of ischemia encouraging growth of immature leaky vessels prone to bleed and, thus the development of an intramural hematoma, which impairs luminal blood flow resulting in tissue ischemia and/or infarction. Created with BioRender.com.