Clonal Smooth Muscle Cell Expansion, Autophagy and Vascular Integrity in Aortic Aneurysm Disease

The dissecting aortic aneurysm (AA) is a feared vascular disorder characterized by medial degeneration, false lumen formation, and risk for death due to hemorrhage or end-organ malperfusion. Vascular smooth muscle cells (VSMCs) are known to play a central role in the maintenance of vascular integrity, while defects in their homeostatic functions are conceptualized as potentiators of aneurysmal dilatation^1,2. To date, little is known about how vascular SMCs respond to apoptosis and inflammation in the dissected aorta, nor if they assume a reparative posture which may have evolved to compensate for degenerative changes in the diseased media.

See accompanying article on page XXX

In this issue, Clément et al. use state-of-the-art multicolor lineage tracing models to show for the first time that vascular SMCs undergo clonal expansion in a mouse model of dissecting AA disease³. The authors report that these cells are extensively ‘de-differentiated’ (e.g. downregulate the ‘cell specific’ markers traditionally used to identify SMCs) and upregulate factors involved in phagocytosis, autophagy and the ER stress response. In a parallel set of experiments, the authors also provide evidence that SMC-specific knockout of the classic autophagy factor, Atg5, accelerates SMC apoptosis, inflammation, and ER stress, while hastening aneurysm-related mortality. Correlative human studies suggest that similar pathways may be dysregulated in humans with AA disease, thus implying translational relevance.

These exciting findings bolster the emerging theory that SMC de-differentiation, plasticity and clonal expansion are common themes shared across the spectrum of vascular disorders⁴. In the past five years, sophisticated lineage tracing studies have confirmed this phenomenon occurs in neointimal lesions after carotid ligation⁵, as well as in atherogenesis models induced by high fat diet^{6, 7} or PCSK9 virus⁸. In each case, a relatively small number of cells appear to be ‘selected’ and give rise to the developing lesion. While the first salvo of mechanistic studies have begun to identify factors involved in clonal expansion (such as integrin beta3 in the case of atherosclerosis)⁷, it remains to be seen what other upstream pathways confer a ‘stem-like’ or proliferative advantage to those cells, or if they may even possess the intrinsic ability to actively suppress neighboring cells that do not clonally expand⁹. In the current study, the authors explicitly rule out a role for TGF-β signaling in clonal expansion, and make the interesting observation that patches of SMCs tend to co-localize with false vascular channels and areas of hemorrhage and iron staining. These data raise the possibility that local environmental stimuli may trigger cellular growth, much like changes that occur with other stem cell ‘niches’.

The other provocative question raised by this article is whether clonal SMC expansion is occurring to protect the blood vessel, if it is a maladaptive response that potentiates disease, or if it depends on the context of the injury. In the case of atherosclerosis, SMC expansion could be viewed as helpful it those cells stabilize the vulnerable cap and prevent plaque rupture, or could accelerate lesion expansion if those cells are inflammatory and contribute to the enlarging necrotic core. In the current study, the authors suggest that clonal expansion may be occurring in an attempt to specifically promote vascular integrity in the setting of a dissection. This could be achieved via multiple mechanisms, assuming those clones replace the structural SMCs that are presumed to be lost from the media during aneurysm formation (due to high levels of programmed cell death), and/or if they augment autophagy pathways which limit (IRE)1α-dependent inflammation while enhancing SMC survival. It is also notable that the clonally expanded SMCs upregulate phagocytic markers, given the recent observation that programmed cell removal is impaired in AA disease, and that ‘pro-efferocytic’ therapies which augment the clearance of apoptotic SMCs are highly protective against aneurysmal degeneration^{10, 11}.

Findings from this study will almost certainly stimulate additional mechanistic efforts and move us closer toward a new translational therapy for aortic aneurysm disease. A causal link between clonal expansion and SMC autophagy can be tested by crossing the Myh11-CreERt2/ROSA26-Confetti lineage tracer with an Atg5^flox/flox mouse model. Such studies will allow the field to confirm that a SMC-restricted autophagy deficiency regulates SMC phenotypic switching during AA progression, and that the developing SMC clones alter vascular biology by regulating ER stress. Particularly if coupled with additional translational studies designed to determine whether imbalanced X chromosome inactivation and/or somatic mutations occur in human AA samples^{12, 13}, we expect that further elucidation of the autophagy-SMC plasticity axis could have high clinical significance and allow for the design of a nonsurgical treatment for AA disease.