Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec 23:12:771960.
doi: 10.3389/fphys.2021.771960. eCollection 2021.

Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation

Maarten M Brandt  1 , Caroline Cheng  1   2 , Daphne Merkus  1   3   4 , Dirk J Duncker  1 , Oana Sorop  1
Affiliations
Review

Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation

Maarten M Brandt et al. Front Physiol. .

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.

Keywords: coronary blood flow; endothelial dysfunction; ischemic heart disease; microvascular density; microvascular disease; microvascular dysfunction; microvascular remodeling.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Influences of metabolic, neurohumoral, endothelium-derived and mechanical factors on the microvasculature. Adapted with permission from Duncker and Bache (2008). ACh, acetylcholine; ATP, adenosine triphosphate; EETs, epoxyeicosatrienoic acids; ET-1, endothelin-1; H2O2, hydrogen peroxide; NE, norepinephrine; NO, nitric oxide; pCO2, dissolved carbon dioxide; PGI2, prostacyclin; pO2, oxygen tension.
Figure 2
Figure 2
Schematic representation of inward and outward hypotrophic, eutrophic and hypertrophic vascular remodeling. Adapted with permission from Mulvany et al. (1996).
Figure 3
Figure 3
Schematic representation of vascular mechanosensing and signal transduction cascades. Akt, protein kinase B; AP-1, activator protein 1; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; eNOS, endothelial nitric oxide; ERK, extracellular signal-regulated kinases; GTP, guanosine triphosphate; JNK, jun N-terminal kinase; KLF2, krüppel-like Factor 2; NF-κB, nuclear factor-κB; NOX, nicotinamide adenine dinucleotide phosphate oxidase; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-like 2; PGI2, prostacyclin; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; RhoA, Ras homolog family member A; ROS, reactive oxygen species; YAP/TAZ, yes-associated protein/transcriptional coactivator with PDZ-binding motif.
Figure 4
Figure 4
Schematic overview of functional and structural coronary microvascular alterations in the presence of classic risk factors. Red arrows refer to changes in vascular function, whereas black arrows refer to vascular remodeling. ANG II, Angiotensin II; ET-1, endothelin-1.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aboualaiwi W. A., Takahashi M., Mell B. R., Jones T. J., Ratnam S., Kolb R. J., et al. . (2009). Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ. Res. 104, 860–869. doi: 10.1161/CIRCRESAHA.108.192765, PMID: - DOI - PMC - PubMed
    1. Adler A., Messina E., Sherman B., Wang Z., Huang H., Linke A., et al. . (2003). NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. Am. J. Physiol. Heart Circ. Physiol. 285, H1015–H1022. doi: 10.1152/ajpheart.01047.2002, PMID: - DOI - PubMed
    1. Amiri F., Virdis A., Neves M. F., Iglarz M., Seidah N. G., Touyz R. M., et al. . (2004). Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 110, 2233–2240. doi: 10.1161/01.CIR.0000144462.08345.B9, PMID: - DOI - PubMed
    1. Antfolk D., Sjoqvist M., Cheng F., Isoniemi K., Duran C. L., Rivero-Muller A., et al. . (2017). Selective regulation of Notch ligands during angiogenesis is mediated by vimentin. Proc. Natl. Acad. Sci. U. S. A. 114, E4574–E4581. doi: 10.1073/pnas.1703057114, PMID: - DOI - PMC - PubMed
    1. Asanuma K., Magid R., Johnson C., Nerem R. M., Galis Z. S. (2003). Uniaxial strain upregulates matrix-degrading enzymes produced by human vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 284, H1778–H1784. doi: 10.1152/ajpheart.00494.2002, PMID: - DOI - PubMed

LinkOut - more resources