Lecture #25: Molecular Physiology of Vascular Smooth Muscle Cells

What are the basic structural characteristics of vascular smooth muscle cells (VSMCs)?

VSMCs are spindle-shaped cells with a single nucleus. They are nonstriated, are not organized into sarcomeres, lack troponin, contain calmodulin, and use dense bodies instead of Z disks.

What replaces troponin in vascular smooth muscle contraction?

Calmodulin. Ca2+ binds calmodulin in VSMCs, whereas troponin participates in Ca2+-dependent contraction in cardiac muscle.

What structures replace Z disks in VSMCs?

Dense bodies replace Z disks. They are located in the cytoplasm and at the cell membrane and provide anchoring sites for the contractile apparatus.

What are the major cytoskeletal filaments in VSMCs?

Thin filaments contain actin, thick filaments contain myosin, and intermediate filaments contain desmin and vimentin.

What is the function of desmin and vimentin in VSMCs?

These intermediate filaments support smooth muscle cell shape and help hold dense bodies in place.

What is the normal phenotype of a VSMC?

Normal VSMCs have a spindle shape, are contractile, nonproliferating, and nonmigrating.

What phenotypic changes occur in diseased VSMCs?

Diseased VSMCs become rhomboid-shaped, secretory/synthetic, proliferating, and migrating. The synthetic phenotype produces extracellular matrix.

What role do VSMCs have in atherosclerotic plaques?

VSMCs contribute to formation of the fibrous portion of atherosclerotic plaques.

How can endothelial damage promote VSMC proliferation and migration?

Endothelial damage decreases nitric oxide, which promotes VSMC proliferation and migration and can contribute to vascular disease and restenosis.

Why is vascular smooth muscle considered involuntary muscle?

VSMC activity is controlled by the autonomic nervous system, although smooth muscle can initiate its own contraction and neurotransmitters and hormones can modify contraction rate and strength.

What is the latch state of smooth muscle?

The latch state allows smooth muscle to remain contracted for long periods without fatigue.

What is myogenic tone?

Myogenic tone is spontaneous vascular tone originating from the smooth muscle itself rather than from autonomic nerves or hormonal processes.

How does increased intraluminal pressure affect small blood vessels?

Increased intraluminal pressure causes vasoconstriction as part of the myogenic response.

How does decreased intraluminal pressure affect small blood vessels?

Decreased intraluminal pressure causes vasodilation as part of the myogenic response.

What neurotransmitter is released by sympathetic fibers onto VSMCs?

Norepinephrine, which acts through alpha-1 and alpha-2 adrenergic receptors to regulate vascular smooth muscle contraction.

What is the key intracellular signal initiating VSMC contraction?

An increase in cytosolic Ca2+ is the key signal initiating contraction.

What happens immediately after cytosolic Ca2+ increases during VSMC contraction?

Ca2+ binds calmodulin, forming a Ca2+-calmodulin complex that activates myosin light-chain kinase (MLCK).

What is the high-yield sequence of VSMC contraction?

↑ cytosolic Ca2+ → Ca2+ binds calmodulin → activation of MLCK → phosphorylation of myosin light chain → myosin binds actin → contraction by the sliding-filament mechanism.

What enzyme directly promotes VSMC contraction?

Myosin light-chain kinase (MLCK) promotes contraction by phosphorylating the myosin light chain.

What activates myosin light-chain kinase?

The Ca2+-calmodulin complex activates MLCK when cytosolic Ca2+ is elevated.

What does MLCK do to myosin?

MLCK phosphorylates the myosin light chain, allowing myosin heads to interact with actin and generate contraction.

How long does VSMC contraction continue?

Contraction continues as long as myosin remains phosphorylated.

What is the role of myosin light-chain phosphatase (MLCP)?

MLCP dephosphorylates myosin light chains, promoting VSMC relaxation.

How do MLCK and MLCP differ in their activity?

MLCK is active when cytoplasmic Ca2+ is elevated through Ca2+-calmodulin signaling, whereas MLCP is always active.

What intracellular event promotes VSMC relaxation?

Dephosphorylation of myosin by myosin light-chain phosphatase promotes relaxation.

Where does the Ca2+ required for VSMC contraction come from?

VSMCs obtain Ca2+ from both the extracellular fluid and intracellular stores in the sarcoplasmic reticulum.

Which channels provide extracellular Ca2+ to VSMCs?

Extracellular Ca2+ enters through voltage-gated L-type Ca2+ channels and voltage-independent channels, including ligand-gated, stretch-activated, and leak channels.

How is Ca2+ released from intracellular stores in VSMCs?

Intracellular Ca2+ can be released from the sarcoplasmic reticulum through Ca2+-induced Ca2+ release and IP3-mediated Ca2+ release.

What is the role of IP3 in VSMCs?

IP3 promotes release of Ca2+ from the sarcoplasmic reticulum, increasing cytosolic Ca2+ and supporting contraction.

What mechanisms remove Ca2+ from the VSMC cytoplasm?

Cytosolic Ca2+ is removed by the plasma-membrane Na+/Ca2+ exchanger, plasma-membrane Ca2+ pump, and sarcoplasmic-reticulum Ca2+-ATPase (SERCA).

What is the role of SERCA in VSMCs?

SERCA pumps cytosolic Ca2+ back into the sarcoplasmic reticulum, lowering cytosolic Ca2+ and promoting relaxation.

What proteins help store Ca2+ within the sarcoplasmic reticulum?

Calsequestrin and calreticulin are Ca2+-binding proteins that help store Ca2+ within the sarcoplasmic reticulum.

What must occur for VSMC relaxation after a contractile stimulus ends?

Ca2+ must be removed from the cytoplasm so intracellular Ca2+ returns toward its resting level.

What is the high-yield sequence of VSMC relaxation?

Ca2+ extrusion/reuptake → ↓ cytosolic Ca2+ → ↓ Ca2+-calmodulin complexes → ↓ MLCK activity → MLCP dephosphorylates myosin light chain → relaxation.

How does decreased cytosolic Ca2+ reduce contraction?

Lower Ca2+ decreases formation of Ca2+-calmodulin complexes, which decreases MLCK activity and allows MLCP-mediated myosin dephosphorylation to favor relaxation.

How does prostacyclin cause VSMC relaxation?

Prostacyclin activates a G-protein signaling pathway that stimulates adenylate cyclase, increases cAMP, activates protein kinases, and promotes vasodilation.

How does sodium nitroprusside cause VSMC relaxation?

Sodium nitroprusside provides NO signaling in VSMCs; NO activates guanylyl cyclase, increasing cGMP and promoting relaxation and vasodilation.

How does KCl cause VSMC contraction?

KCl depolarizes the VSMC membrane potential, activating Ca2+ signaling and producing contraction.

Why does membrane depolarization cause VSMC contraction?

Depolarization activates L-type Ca2+ channels in the plasma membrane, allowing extracellular Ca2+ influx that promotes the Ca2+-calmodulin-MLCK contraction pathway.

Which drugs in the lecture block L-type Ca2+ channels?

Nifedipine, amlodipine, and verapamil are listed as L-type Ca2+ channel blockers.

How would an L-type Ca2+ channel blocker affect KCl-induced VSMC contraction?

It would reduce KCl-induced contraction by decreasing the extracellular Ca2+ influx that follows membrane depolarization.

What is the role of L-type Ca2+ channels in cardiac and smooth muscle?

Depolarization activates plasma-membrane L-type Ca2+ channels, causing extracellular Ca2+ influx that contributes to contraction in both cardiac and smooth muscle.

What does Ca2+ bind to in smooth muscle versus cardiac muscle?

Ca2+ binds calmodulin in smooth muscle but binds troponin in cardiac muscle.

How do skeletal muscle L-type Ca2+ channels differ from those in VSMCs?

In skeletal muscle, L-type Ca2+ channels mechanically interact with ryanodine receptors to release SR Ca2+ without requiring significant extracellular Ca2+ influx; VSMCs depend on extracellular Ca2+ influx through L-type channels.

Why do L-type Ca2+ channel blockers not significantly affect skeletal muscle contractility according to the lecture?

Skeletal muscle contraction is not dependent on significant extracellular Ca2+ influx through L-type channels because these channels mechanically activate SR ryanodine receptors.

What relationship between myosin phosphorylation and vascular tone is most important?

Phosphorylated myosin favors actin-myosin interaction and contraction, whereas dephosphorylated myosin favors relaxation.

What are the major mechanisms controlling vascular diameter emphasized in this lecture?

Vascular diameter is regulated by changes in VSMC cytosolic Ca2+, Ca2+-calmodulin activation of MLCK, myosin phosphorylation/dephosphorylation, autonomic signaling, myogenic tone, and vasodilatory pathways.

What are the most important concepts from Lecture #25?

Know the VSMC contractile proteins, Ca2+-calmodulin-MLCK contraction pathway, sources and removal of Ca2+, MLCP-mediated relaxation, KCl-induced depolarization and L-type Ca2+ influx, sodium nitroprusside-mediated relaxation, and normal versus diseased VSMC phenotypes.