Connexin expression is sensitive to cell state and varies with cell and vessel type. Connexin protein expression in situ is typically defined by immunohistochemical localization or by immunoblot. However, cross-reactivity between antibodies, particularly cross-reactivity of anti-Cx40 antibodies to Cx43, is a potential concern when considering analysis of connexin expression in the vasculature.
Gap junctions are more prominent in large than small vessels. Interendothelial and inter-smooth muscle junctions are homologous, whereas endothelial-smooth muscle junctions are heterologous. Cx37 and Cx40 are uniformly expressed by vascular endothelial cells in situ. However, endothelial expression of Cx37 and Cx43 is greater in large than in small vessels. Endothelial Cx43 expression might be species-specific, since the expression is pronounced in rat and bovine aortic endothelium, but less prominent in mouse aortic endothelium. Also, Cx43 expression is higher in areas with turbulent flow, such as at vessel branch points.
Cx43 is the most prominent connexin expressed by vascular smooth muscle. Low levels of Cx37 expressed by resting vascular smooth muscle may be upregulated during new vessel growth. Other connexins expressed by vascular smooth muscle include Cx45, which is limited to specific vascular beds such as cerebral vessels and ascending aorta of rat, and the recently identified Cx31.9.
Heteromer formation is likely to be important for formation of functional myo-endothelial gap junctions since endothelial Cx37: Cx40 hemichannels are linked to vascular smooth muscle hemichannels containing mainly Cx43 to form well-coupled heterotypic gap junctions. In the absence of Cx37, homomeric Cx40 hemichannels expressed by endothelium and Cx43 hemichannels expressed by vascular smooth muscle would form poorly conducting heterotypic gap junction channels.
Knockout models indicate that the coordinated expression of connexin subtypes is complex in the vascular bed.
In one study, endothelial cell-cell coupling was maintained in Cx40-deficient mice by compensatory upregulation of endothelial Cx37, but not Cx43 . However, Cx37 deficiency had little effect on Cx40 or Cx43 expression or on cell coupling. Although Cx37 or Cx40 deficiency alone has little effect on vessel morphology, mice doubly deficient in Cx37 and Cx40 die soon after birth and show abnormally dilated blood vessels, particularly in skin and testis . Vessels in Cx37 -/- Cx40 -/- mice also have permeability defects and localized hemorrhages, suggesting a role for endothelial gap junctions in regulating vessel barrier function. Cx43 deficiency does not affect global vascular development, although coronary artery development is partially defective . Although Cx45 expression in the vascular bed is limited, it plays a critical, yet undetermined, role in vessel development during embryogenesis since Cx45-deficient mice have defective vascular branching and do not develop smooth muscle in large vessels.
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