Blood Vessels & Smooth Muscle Cells
Vessels are the pipeline for transporting blood throughout the body. Blood, in turn, carries oxygen, nutrients, water, and other chemicals to tissues and organs throughout the body. The blood vessel is comprised of three main layers, the tunica intima, the tunica media, and the tunica adventitia. All three layers play a unique role in both physiological homeostasis and in pathological conditions. In this post, we will briefly focus on the role that the key constituents of the tunica media layer, the smooth muscle cells (SMCs), play in vascular disease pathogenesis.
The tunica media is the muscular layer of the blood vessel. It contains SMCs which contain contractile and contractile-related proteins such as smooth muscle myosin heavy chain (SMMHC/Myh11), α-smooth muscle actin (αSMA/Acta2), SM22α (Tagln1), and calponin (Cnn1). Under physiological conditions, SMCs help regulate body temperature and blood pressure through blood vessel vasoconstriction and vasodilation. However, SMCs also play a key role in many vascular pathological conditions, including atherosclerosis and pulmonary hypertension.
Hemodynamics & SMCs in Vascular Disease
There are a variety of factors that can potentially contribute to the etiology of vascular diseases, including inflammation, genetic mutations, and altered metabolism, to name a few. However, one often underestimated potential causative factor is blood flow mechanics or hemodynamics. Altered blood flow and hemodynamics can create pathological environments that can increase the risk of disease. For example, continuous high blood pressure or high flow due to either 1) chronically occurring pulmonary embolism, 2) chronic stimulant use, 3) congenital heart defects, 4) exposure to chronic hypoxic environments or 5) use of left-ventricular assist devices, can all potentially cause vascular complications such as pulmonary hypertension or atherosclerosis.1, 2, 3, 4
The mechanisms for why altered blood flow causes vascular complications is a bit unclear. It may induce cell signaling changes. It may also physically disrupt vessels, as they are only meant to handle physiological blood flow mechanics. However, some researchers at the University of Colorado have at least found one mechanism for how altered blood flow results in vascular complications, and this mechanism is related to the phenotype and epigenetic profile of SMCs.
Under physiological conditions, SMCs exhibit phenotypic plasticity, and depending on the stimuli, can transition from a differentiated state into a dedifferentiated state. This plasticity is not present in the “muscle” cells of cardiac and skeletal tissue. According to Moulton et al., “SMC dedifferentiation is associated with a transition to a highly proliferative, inflammatory phenotype characterized by downregulation of SMC-specific genes and increased production of multiple inflammatory and extracellular matrix–associated (ECM-associated) mediators. Thus, SMCs are major contributors to pathological vascular remodeling and vascular disease progression, and defining molecular mechanisms regulating SMC phenotypic transitions is critical to identify novel therapeutics for the treatment or regression of atherosclerosis.”
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and plays a role in maintaining vascular homeostasis. PTEN has been identified as one of the most commonly downregulated genes in human coronary and carotid atherosclerotic arteries. Its main function is to dephosphorylate PIP3, which inactivates the PI3-kinase/Akt pathway. Interestingly, the PI3-kinase/Akt pathway is activated in conditions like PH.4, 5
PTEN also plays a role, however, in SMC regulation. Normally, SMCs are under transcriptional control by the transcription factor, serum response factor (SRF), and the cofactor myocardin. Researchers have demonstrated that PTEN directly interacts with SRF and myocardin in the cell nucleus to suppress proliferative, inflammatory, and remodeling pathways, and thus help maintain SMC differentiation. PTEN accomplishes this via regulating the expression of contractile genes in SMCs.
In previous experiments, Moulten et al. found a correlation between vascular complications arising from continuous flow left ventricular assist device (CF-LVAD) use. In research published in JCI Insight, the researchers explored the relation further, with an eye on SMCs, and PTEN, as a culprit. Their key findings are summarized below.
- PTEN is correlated with alpha SMA, a marker of differentiation. Low PTEN and alpha SMA levels are found in atherosclerotic plaques.
- Mice with SMC specific PTEN knockout experience exacerbated restenosis and accelerated atherosclerosis.
- CF-LVAD patients have increased vessel stiffness and increased collagen deposition.
- SMC-specific PTEN depletion in mice promotes vascular fibrosis.
- SMC-specific PTEN was found to be reduced in nonatherosclerotic hyperplasia vessels from patients using CF-LVAD compared with patients not using CF-LVAD. Moreover, medial fibrosis was observed in nonatherosclerotic hyperplasia vessels from patients using CF-LVAD compared with patients not using CF-LVAD.
- Deactivation of PTEN results in a proinflammatory phenotype, as defined by increased expression of IL-6, MCP-1/CCL2, CXCL1, and SDF-1α/CXCL12.
- A plethora of altered cytokine/chemokine and ECM genes were identified in PTEN-deficient SMCs:
- “…the cytokine/chemokine–related genes Il6, Ccl2, Cxcl13, and Tgfa, and the ECM-related mRNAs Fbln1, Col6a3, Vcan, Col4a1, and Col4a2, were found to be upregulated in PTEN-deficient SMCs compared with controls (Figure 9A). Similarly, Cx3cl1, Il15 (previously demonstrated to have antifibrotic properties; see ref. 40), Fbln2, Matn2, and Fbln5 were found to be downregulated in PTEN-deficient SMCs compared with controls (Figure 9B). Eln, shown as downregulated by microarray assessment, consistently was found upregulated in PTEN-deficient SMCs compared with controls using qPCR approaches (Figure 9C).”
From these results, it appears that altered hemodynamic forces can result in SMC PTEN deficiency, which is then associated with SMC dedifferentiation and vascular fibrosis.
Apparently, “PTEN inactivation results in downregulation of SMC-specific contractile genes and a global gene expression signature that is proinflammatory and profibrotic, hallmarks of SMC dedifferentiation observed in diseased vessels.” Interestingly, PH SMCs also have a lower expression of contractile proteins and thus less of a contractile phenotype.6
It is now recognized that atherosclerosis is an immune condition, and heavily involves SMCs, specifically, the cytokine and chemokines that are released from SMCs, which can interact with immune cells. Anything that promotes SMC dedifferentiation and this proinflammatory phenotype can set the stage for atherogenic processes. If altered hemodynamics promotes PTEN loss, which then promotes SMC dedifferentiation than this suggests that altered hemodynamics can contribute to atherosclerosis.
The authors conclude that the data obtained from their studies “data highly support a role for PTEN in human vessels as an anti-inflammatory and antifibrotic target that functions to maintain the SMC differentiated phenotype. Interestingly, recent unpublished data from our lab demonstrate that systemic PTEN overexpression in mice blocks angiotensin-mediated cardiovascular fibrosis and accumulation of immune cells (Lu, et al., unpublished data) as well as atherosclerosis progression (Moulton, et al., unpublished data), further supporting this proposal. Moreover, previous studies examining the tumor suppressive functions of PTEN demonstrated that systemic elevation of PTEN results in a healthy and tumor suppressive anti-Warburg phenotype, reduced fat accumulation, and increased mitochondrial oxidative phosphorylation (45, 46). Collectively, these findings support the concept that systemic pharmacological upregulation of PTEN is a potentially novel and viable approach to prevent the detrimental structural and functional vascular changes associated with atherosclerosis or as observed in patients supported with CF-LVADs.”
- If altered blood flow/hemodynamics reduces PTEN, and PTEN loss results in vascular complications, how exactly does altered blood flow mechanics reduce PTEN?
- The authors found dramatic changes in the adventitia of artery samples from patients using CF-LVAD. Also, the adventitia in PTEN deficient mice was found to be significantly remodeled. However, is this a cause or consequence of SMC-specific PTEN reduction, or is another mechanism occurring?
- Aside from pharmacological and therapeutic approaches, are there any epigenetic ways to promote PTEN stability/gene expression? Exercise, foods, supplements?