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Page 4 of 13 Ahmed et al. Vessel Plus 2018;2:36 I http://dx.doi.org/10.20517/2574-1209.2018.51

Figure 2. Calcium dependent and independent regulation of VSMC contraction. The two pathways work synergistically. Calcium
dependent regulation is associated with transient phasic contraction whereas RhoA/ROCK regulation is associated with the prolonged
tonic contraction of VSMCs. GPCR: G-protein coupled receptor; IP3: inositol triphosphate; SR: sarcoplasmic reticulum; Rho GEF:
RhoGTPase guanine nucleotide exchange factors; ROCK: Rho-associated protein kinase; MLC: myosin light chain; VSMC: vascular
smooth muscle cell

[35]
muscle myosin II (NM-myosin II), which is upregulated in the proliferative state . NM-myosin II is also
expressed in the differentiated state, albeit at lower levels. Once phosphorylated, myosin associates with
actin filaments to form the actomyosin complex. The ATPase activity of the myosin then results in rapid
cycling of the cross-bridges formed between actin and myosin, thus causing a pulling of the actin thin
[36]
filaments . The physiological function of the two myosin isoforms vary and the SM-myosin II has a higher
[37]
immune-reactivity in tissue areas where faster phasic VSMC contractions were occurring . This is in
[37]
contrast to NM-myosin II, which primarily regulates the slower tonic phase of VSMC contraction . The
tonic contraction induced from NM-myosin II generates less force than phasic contraction produced from
SM-myosin II [37,38] .

VSMC CONTRACTION
Calcium-dependent pathway
VSMC contraction occurs via two interlinked pathways that contribute synergistically to the contractile
properties of VSMCs [Figure 2]. The first pathway, more commonly known as the calcium-dependent
pathway, primarily involves augmenting cytoplasmic calcium levels to induce phasic contraction. Increased
intracellular calcium can be triggered by mechanical, electrical and chemical stimuli, either by calcium
influx from channels located on the plasma membrane or by release of calcium from the sarcoplasmic
[39]
reticulum (SR) . Calcium entry from the extracellular space usually occurs via voltage gated calcium
channels (VGCCs) or non-selective cation channels. Sub-populations of L-type, P/Q-type and T-type
[40]
VGCCs are all found within VSMCs and are activated via depolarization . In addition, non-selective cation
channels, found to predominantly be members of the transient receptor potential canonical family, allow for
[40]
2+
+
Na and Ca influx following receptor occupancy or capicitative calcium entry .
Release of calcium from the SR is predominantly mediated by the activation of G-protein coupled receptors
(GPCRs) (i.e., the AT1 receptor) coupled to the Gaq G-protein. The Gaq protein, when in its GTP-bound
state, causes activation of phospholipase C which hydrolyses phosphatidylinositol 4,5-bisphosphate
(PIP2) into inositol triphosphate (IP3) and diacylglycerol [41,42] . IP3 binds to the IP3 receptors present on