Abstract
The coronary microvasculature plays a key role in regulating the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity. Short-term regulation of coronary blood flow in response to metabolic stimuli is achieved via adjustment of vascular diameter in different segments of the microvasculature in conjunction with mechanical forces eliciting myogenic and flow-mediated vasodilation. In contrast, chronic adjustments in flow regulation also involve microvascular structural modifications, termed remodeling. Vascular remodeling encompasses changes in microvascular diameter and/or density being largely modulated by mechanical forces acting on the endothelium and vascular smooth muscle cells. Whereas in recent years, substantial knowledge has been gathered regarding the molecular mechanisms controlling microvascular tone and how these are altered in various diseases, the structural adaptations in response to pathologic situations are less well understood. In this article, we review the factors involved in coronary microvascular functional and structural alterations in obstructive and non-obstructive coronary artery disease and the molecular mechanisms involved therein with a focus on mechanobiology. Cardiovascular risk factors including metabolic dysregulation, hypercholesterolemia, hypertension and aging have been shown to induce microvascular (endothelial) dysfunction and vascular remodeling. Additionally, alterations in biomechanical forces produced by a coronary artery stenosis are associated with microvascular functional and structural alterations. Future studies should be directed at further unraveling the mechanisms underlying the coronary microvascular functional and structural alterations in disease; a deeper understanding of these mechanisms is critical for the identification of potential new targets for the treatment of ischemic heart disease.
Highlights
The coronary microvasculature plays a key role in the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity
We discussed the involvement and consequences of biomechanical signal transduction cascades on functional and structural modifications of the coronary microvasculature and how they are influenced by the different risk factors (Figure 4)
ischemic heart disease (IHD) patients often present with different combinations of these risk factors, and most likely benefit from a tailored therapeutic approach focussed at normalization of hemodynamics or restoration of mechanotransduction, it has become apparent that certain mechanistic and phenotypic aspects of coronary microvascular dysfunction overlap
Summary
The coronary microvasculature plays a key role in the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity. The exact nature of the factors and mechanisms responsible for local microvascular metabolic tone control is still not completely understood (Deussen et al, 2012), but several tissue-derived metabolites have traditionally been proposed to play a role in the regulation of coronary microvascular resistance during increased metabolic demand These include dissolved O2 and CO2, as well as adenosine, involving activation of various K+ channels (Gerlach and Deuticke, 1966; Tune, 2007; Goodwill et al, 2017), the specific contribution of each type of K+ channel remains a matter of debate. Integrinmediated activation of RhoA stimulates yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), initiating the transcription of a variety of inflammatory genes by activating AP-1 via jun n-terminal kinase (JNK; Wang et al, 2016b)
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