Structural control of fibrin bioactivity by mechanical deformation

Abstract

Significance Fibrin plays a vital role in biology as the fibrous network that stabilizes blood clots and also through interaction with numerous blood components. While much is known about fibrin mechanics, comparatively little is known about how fibrin’s mechanics influence its biochemistry. We show that structural changes in fibrin under mechanical tension reduces binding of tissue plasminogen activator, an enzyme that initiates lysis. Furthermore, these structural transitions also led to decreased platelet activation through suppressed binding between platelet integrins and fibrin. Our work shows that fibrin possesses an intrinsic mechano-chemical feedback loop that regulates its bioactivity via molecular structural rearrangements.

Clots reveal anomalous elastic behavior of fiber networks

“…5F show that the manner in which platelet contractility influences modulus (specifically the G ′ ratio for uncross-linked versus cross-linked fibers) is dependent on the magnitude of strain. This may arise because of the adaptive dependence of platelet contractile force on network stiffness ( 60 ) or enhanced fibrin stability under stress ( 61 ), through which platelets possibly exert lower initial force, e.g., 15 nN, at low strains (below 1%), and exert higher force at intermediate strains (1 to 10%). Such mechano-adaptation is typical in contractile cells that exert greater traction force when the extracellular environment is stiffer.…”

Elucidating the role of water in collagen self-assembly by isotopically modulating collagen hydration

“…3 A ) in H 2 O and D 2 O using infrared (IR), two-dimensional IR (2D-IR), circular dichroism (CD) spectroscopy and molecular dynamics (MD) simulations. IR and 2D-IR spectroscopy probe the local structure and solvation by studying the infrared absorption bands of amide I modes ( 33 – 35 ), CD spectroscopy probes the helicity ( 36 , 37 ) and the stability ( 38 ) of collagen, and MD simulations provide insight into the structural details of the monomer in different solvents.…”

Visualizing molecular deformation in fibrin networks under tensile loading via FLIM–FRET

“…Interestingly, we observed a 2.14-fold increase of the longer lifetime's subcategory contribution (42.8 ns) from 100% to 160% strain, where the coiled coils in fibrin molecules are known to undergo secondary structural transitions. 8 A second observation is the alignment of fibrin fibers with load and the relation with donor lifetime (Fig. 4a and b).…”

“…For instance, fibrin fibers under external mechanical loads exhibit different orientations, thicknesses, and molecular structures, which can ultimately regulate the downstream biological readouts at the enzymatic and cellular levels. [6][7][8] Cellular receptors and enzymes that interact with fibrin do so via molecular-scale contacts. However, the mechanisms connecting physical and molecular changes in fibrin and downstream biochemical signaling are unclear.…”

“…Interestingly, we observed a 2.14-fold increase of the longer lifetime's subcategory contribution (>2.8 ns) from 100% to 160% strain, where the coiled coils in fibrin molecules are known to undergo secondary structural transitions. 8…”